WO2023141236A2 - Méthodes de traitement de cancers de la vessie par instillation intravésicale d'un poliovirus chimérique - Google Patents

Méthodes de traitement de cancers de la vessie par instillation intravésicale d'un poliovirus chimérique Download PDF

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WO2023141236A2
WO2023141236A2 PCT/US2023/011184 US2023011184W WO2023141236A2 WO 2023141236 A2 WO2023141236 A2 WO 2023141236A2 US 2023011184 W US2023011184 W US 2023011184W WO 2023141236 A2 WO2023141236 A2 WO 2023141236A2
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administered
inhibitor
wash
bladder
poliovirus
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WO2023141236A3 (fr
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William Garett NICHOLS
Shannon Morris
Lena Britt Maria EVILEVICH
Jessica A. SORRENTINO
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Istari Oncology, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/76—Viruses; Subviral particles; Bacteriophages
    • A61K35/768—Oncolytic viruses not provided for in groups A61K35/761 - A61K35/766
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/32011—Picornaviridae
    • C12N2770/32611—Poliovirus
    • C12N2770/32621—Viruses as such, e.g. new isolates, mutants or their genomic sequences
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/32011—Picornaviridae
    • C12N2770/32611—Poliovirus
    • C12N2770/32632—Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/32011—Picornaviridae
    • C12N2770/32611—Poliovirus
    • C12N2770/32661—Methods of inactivation or attenuation
    • C12N2770/32662—Methods of inactivation or attenuation by genetic engineering
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/32011—Picornaviridae
    • C12N2770/32711—Rhinovirus
    • C12N2770/32721—Viruses as such, e.g. new isolates, mutants or their genomic sequences
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2840/00—Vectors comprising a special translation-regulating system
    • C12N2840/20—Vectors comprising a special translation-regulating system translation of more than one cistron
    • C12N2840/203—Vectors comprising a special translation-regulating system translation of more than one cistron having an IRES
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to improved methods for treating bladder cancer, including nonmuscle invasive bladder cancer, (NMIBC) by altering the tumor microenvironment to promote a pro-inflammatory immune response to the tumor via specifically timed intravesical instillation administrations of a chimeric poliovirus.
  • NMIBC nonmuscle invasive bladder cancer
  • Cancer of the bladder also known as urological cancer and urinary bladder cancer, is the 10 th most common cancer worldwide and 13 th most deadly, with the incidence rate rising globally (Saginala et al. Med Sci. 8(1): 15(2020)). Within the United States, it was estimated that approximately 81,000 patients would be diagnosed with, and 18,000 patients would die from, bladder cancer in 2020, with around 75% of the cases occurring in men with an average diagnosis age of 73 years (Richters et al. World J Urol. 38(8): 1895-1904(2020)).
  • bladder cancer cases arise from urothelial cells that line the bladder and urinary tract (termed urothelial carcinoma or transitional cell carcinoma), with the strongest risk factors being tobacco smoking (-65% of cases) or occupational or environmental hazards (20% of cases).
  • the remaining cases are attributed to squamous cell bladder cancer (due to the protozoan infection schistosomiasis) or rare subtypes such as adenocarcinoma, sarcoma, and metastases to the bladder (Saginala et al. Med Sci. 8(1): 15(2020)).
  • Non-muscle invasive bladder cancer comprises noninvasive papillary carcinomas (Ta; 48%), submucosal invasive tumors (Tl; 27%), carcinoma in situ (CIS; 2%) or some combination of these types (Boustead et al. BJU Int. 113 (6): 924-30(2014); Chang et al. J Urol. 196(4): 1021-9(2016)); and may be categorized as low-, intermediate-, or high risk of experiencing recurrence and/or progression of bladder cancer (Table 1). These risk categories are intended to guide clinicians in treatment and surveillance decisions based on disease prognosis.
  • AUA Risk Stratification for Bladder Cancer Recurrence and/or Progression Transurethral resection of all visible lesions is a standard treatment for NMIBC (Babjuk et al. Eur Urol. 71(3):447-61(2016)) but is accompanied with an exceedingly high tumor recurrence rate ranging from 50% to 70% as well as a high tumor progression rate into muscle-invasive bladder cancer type between 10% and 20% over a period of 2 to 5 years (Chen et al. Chin Med J. 123(23):3422-6(2010)).
  • guidelines recommend chemotherapy or immunotherapy in the management of NMIBC to reduce these risks of recurrence and progression (Babjuk et al. Eur Urol. 71(3):447-61(2016)).
  • Immunotherapies include the intravesical administration of BCG, a live attenuated strain of Mycobacterium bovis.
  • the recommended standard of care for patients with NMIBC involves transurethral resection of bladder tumor (TURBT) followed by intravesical chemotherapy or Bacillus Calmette-Guerin (BCG) non-specific immunotherapy depending on the patient’s risk group (Flaig et al. J Natl Compr Cane Netw. 18(3):329-54(2020); Chang et al. J Urol. 196(4): 1021 - 9(2016); Babjuk et al. Eur Urol. 76(5):639-57(2019)).
  • TURBT transurethral resection of bladder tumor
  • BCG Bacillus Calmette-Guerin
  • Low-risk tumors are conventionally managed with single dose intravesical chemotherapy while high-risk tumors are managed with adjuvant intravesical BCG (Morales et al. JUrol. 116: 180-3(1976)). Intermediate-risk tumors may be managed with either intravesical chemotherapy or BCG.
  • BCG immunotherapy may decrease the frequency of — and delay the time to — cancer recurrence and progression in patients with NMIBC (Babjuk et al. Eur Urol. 71 (3) :447-61 (2016); Braasch et al. BJU Int. 102: 1254-64(2008)). There remains, however, a 50% failure rate with patients receiving BCG (Packiam et al. Urol Oncol Semin Orig Investig. 36:440-7(2018)). Patients who do not respond to BCG therapy are classified into four refractory subgroups, including BCG refractory, BCG relapsing, BCG unresponsive, and BCG intolerance.
  • Treatment regimens comprising the intravesical administration of chemotherapy agent(s) either in combination with BCG therapy or in patients who have failed BCG therapy have shown some benefit.
  • the chemotherapy agents currently being tested in bladder cancer patients comprise platinum-based drugs including cisplatin and carboplatin and non-platinum-based drugs including mitomycin C, doxorubicin, epirubicin, gemcitabine, docetaxel, methotrexate, vinblastine, and cabazitaxel.
  • a standard of care in NMIBC has been a single post-TURBT intravesical instillation of mytomicin C which has been demonstrated to lower recurrence rate depending on the bladder cancer subtype (Sylvester et al. J Urol. 171 :2186-90(2004)).
  • the present invention provides improved methods to treat bladder cancer, including nonmuscle invasive bladder cancer (NMIBC), in a human subject comprising intravesical instillation administration to the patient of a high dose of a chimeric poliovirus construct comprising a Sabin type I strain of poliovirus with a human rhinovirus 2 (HRV2) internal ribosome entry site (IRES) in the poliovirus 5' untranslated region between the poliovirus cloverleaf and the poliovirus open reading frame (a “chimeric poliovirus”) in the bladder.
  • the chimeric poliovirus is administered by intravesical instillation in a particular treatment regime comprising an induction phase and a maintenance phase.
  • the chimeric poliovirus is lerapolturev (also known as PVSRIPO).
  • Lerapolturev is an oncolytic virus capable of direct anti -tumor effects through the cytotoxic infection of tumor cells. Unlike other oncolytic viruses, however, lerapolturev is also capable of non-1 ethal infection of many immune effector cells, including tumor associated macrophages (TAMs) and dendritic cells (DCs), which express the CD155 poliovirus receptor.
  • TAMs tumor associated macrophages
  • DCs dendritic cells
  • the non-lethal infection of immune effector cells leads to activation of secondary immune responses via triggering of innate interferon (IFN) pathways against tumor neoantigens.
  • IFN innate interferon
  • Upregulation of Type 1 IFN signaling in the TME leads to the generation of a systemic cytotoxic T lymphocyte (CTL) effector anti-tumor response.
  • CTL systemic cytotoxic T lymphocyte
  • infection of immune effector cells with other oncolytic viruses impedes the ability of DCs to mount an antiviral
  • targeted TME cellular infection of bladder cancers such as NMIBC via intravesical instillation using a chimeric poliovirus, for example lerapolturev is not adversely affected by chemicals that model biofluids (e.g., saliva, urine) or supplemental agents (e.g., detergent) (see, e.g., FIG. 1 A-E), rendering delivery via intravesical instillation within the bladder a promising therapeutic approach.
  • Cells infected with lerapolturev are capable of mounting a robust Type 1 interferon beta (IFN-P) immunomodulatory response across a wide variety of environmental conditions (see, e.g., FIG.
  • IFN-P Type 1 interferon beta
  • a specifically-timed administration schedule of a chimeric poliovirus by intravesical instillation may provide enhanced efficacy and reduced tumor recurrence rates in subjects with bladder cancer.
  • a chimeric poliovirus is administered to the subject at specifically timed intervals for the initiation of an immune effector cell response during an induction phase. Following the induction phase, the subject can be further administered the chimeric poliovirus at specific times to maintain or further enhance the immune response to the bladder cancer during a maintenance phase.
  • the chimeric poliovirus comprises lerapolturev.
  • the improved methods herein are effective in subjects who were previously administered anti -cancer therapies but have developed an acquired resistance to such treatment, had a primary resistance to such treatment, have progressed on such treatment, or had a cancer recurrence during or following such treatment.
  • the improved methods herein provide reduced tumor recurrence rates in subjects. In some embodiments, the improved methods herein provide reduced tumor progression rates.
  • an effective amount of a chimeric poliovirus is administered to a subject with bladder cancer during an induction phase, wherein the induction phase comprises one or more treatment cycles, wherein each treatment cycle comprises the administration of the chimeric poliovirus once per week for 6 weeks, and wherein the chimeric poliovirus is administered via intravesical instillation.
  • the induction phase comprises 2 or more treatment cycles.
  • the induction phase comprises 2, 3, 4, 5, or more than 5 treatment cycles.
  • the induction phase comprises 2 treatment cycles.
  • the induction phase comprises 3 treatment cycles.
  • the induction cycle is repeated if no objective response rate (ORR) is exhibited by the patient.
  • the induction cycle is repeated if no complete response (CR) is exhibited by the patient. In some embodiments, the induction cycle is repeated if no partial response (PR) is exhibited by the patient.
  • the subject is administered the chimeric poliovirus in an induction phase only. In some embodiments, the chimeric poliovirus comprises lerapolturev. In some embodiments, the method is administered until disease progression or death.
  • the bladder cancer is non-muscle invasive bladder cancer (NMIBC). In some embodiments, the bladder cancer is muscle invasive bladder cancer (MIBC).
  • an effective amount of a chimeric poliovirus is administered to a subject with bladder cancer during a maintenance phase, wherein the maintenance phase comprises one or more treatment cycles, wherein each treatment cycle comprises the administration of the chimeric poliovirus once a week by intravesical instillation, wherein each treatment cycle lasts 1 -week, 2- weeks, 3 -weeks, 4-weeks, or 6 weeks, and wherein the initiation of each treatment cycle is 4 weeks apart, 6 weeks apart, 8 weeks apart, 10 weeks apart, 3 months apart, or 6 months apart.
  • a treatment cycle of the maintenance phase is administered at the beginning of month 3, month 6, month 12, month 18, month 24, month 30, and month 36 following the initiation of the induction phase.
  • the maintenance phase comprises 2 or more treatment cycles, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 treatment cycles. In some embodiments, the maintenance phase comprises between 2 and 10 treatment cycles. In some embodiments, the maintenance phase comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, or 11 or more treatment cycles. In some embodiments, the maintenance phase comprises 7 treatment cycles.
  • the subject is administered the chimeric poliovirus in a maintenance phase only. In some embodiments, the maintenance phase is administered following the cessation of an induction phase. In some embodiments, the maintenance phase is administered following an objective response rate (ORR) exhibited by the patient following the cessation of the induction phase.
  • ORR objective response rate
  • the maintenance phase is administered following a complete response (CR) exhibited by the patient following the cessation of the induction phase.
  • the method is administered until disease progression or death.
  • the chimeric poliovirus comprises lerapolturev.
  • the bladder cancer is non-muscle invasive bladder cancer (NMIBC).
  • the bladder cancer is muscle invasive bladder cancer (MIBC).
  • an effective amount of a chimeric poliovirus is administered to a subject with bladder cancer during an induction phase as described above, and, following the cessation of the induction phase, an effective amount of a chimeric poliovirus is further administered to the subject in a maintenance phase as described above.
  • the maintenance phase is administered until disease progression or death.
  • the maintenance phase comprises one or more treatment cycles, wherein each treatment cycle comprises the administration of a chimeric poliovirus once a week for 3 weeks, and wherein the chimeric poliovirus is administered to the bladder via intravesical instillation.
  • the maintenance phase comprises one or more treatment cycles, wherein each treatment cycle comprises the administration of a chimeric poliovirus once a week for 2 weeks, and wherein the chimeric poliovirus is administered to the bladder via intravesical instillation. In some embodiments, the maintenance phase comprises one or more treatment cycles, wherein each treatment cycle comprises the administration of a chimeric poliovirus once a week for 1 week, and wherein the chimeric poliovirus is administered to the bladder via intravesical instillation. In some embodiments, the maintenance phase comprises 2 or more treatment cycles, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 treatment cycles. In some embodiments, the maintenance phase comprises between 2 and 10 treatment cycles.
  • the maintenance phase comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, or 11 or more treatment cycles. In some embodiments, the maintenance phase is administered until disease progression or death.
  • the bladder cancer is non-muscle invasive bladder cancer (NMIBC). In some embodiments, the bladder cancer is muscle invasive bladder cancer (MIBC).
  • each treatment cycle of the maintenance phase is administered at least 4 weeks apart. In some embodiments, a treatment cycle of the maintenance phase is administered at the beginning of month 3, month 6, month 12, month 18, month 24, month 30, and month 36 following the start of the induction phase. In some embodiments, each treatment cycle of the maintenance phase is administered at least 4 weeks apart, at least 6 weeks apart, at least 8 weeks apart, at least 10 weeks apart, at least 12 weeks apart, or greater than 12 weeks apart. In some embodiments, each treatment cycle of the maintenance phase is administered at least 1 month apart, at least 2 months apart, at least 3 months apart, at least 4 months apart, at least 5 months apart, at least 6 months apart, or a combination thereof. In some embodiments, the subject is administered a maintenance phase alone. In some embodiments, the bladder cancer is non-muscle invasive bladder cancer (NMIBC). In some embodiments, the bladder cancer is muscle invasive bladder cancer (MIBC).
  • NMIBC non-muscle invasive bladder cancer
  • MIBC muscle invasive bladder cancer
  • the chimeric poliovirus for administration by intravesical instillation in the methods described herein can be administered, for example, as a pharmaceutical composition that includes an effective amount of the chimeric poliovirus, for example lerapolturev, for a subject, typically a human, in need of such treatment in a pharmaceutically acceptable carrier.
  • a pharmaceutical composition that includes an effective amount of the chimeric poliovirus, for example lerapolturev, for a subject, typically a human, in need of such treatment in a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises at least one chimeric poliovirus administered at a high dose by intravesical instillation, for example at a total dose of between about 2.0xl0 8 TCID50 and about 5.OxlO 10 TCID50, for example up to about 2.0xl0 8 TCID50, up to about 2.0xl0 9 TCID50, up to about 5.OxlO 10 TCID50.
  • the total dose administered at each intravesical instillation is between about 2.0xl0 8 TCID50 and about l.OxlO 10 TCID50.
  • the total dose administered at each intravesical instillation is about 8.0xl0 8 to about l.OxlO 10 TCID50.
  • the methods described herein can be used to treat one or more solid bladder tumor(s) comprising administering a chimeric poliovirus at a dose of between about 8.0xl0 8 to about l.OxlO 9 , about l.OxlO 9 to about 3.0xl0 9 , about 3.0xl0 9 to about 5.0xl0 9 TCID50, about 5.0xl0 9 to about 7.0xl0 9 TCID50, or about 7.0xl0 9 to about l.OxlO 10 TCIDso.
  • the methods described herein can be used to treat a solid tumor comprising administering a chimeric poliovirus construct at a dose of about 2.0xl0 9 TCID50 per administration.
  • the pharmaceutically acceptable carrier comprises between about 20 nM and about 80 nM sodium phosphate in between about 0.5% and about 1.5% sodium chloride, with a pH of between about pH 6.8 to about pH 7.8, with between about 0.1% and about 0.5% human serum albumin (HSA) in phosphate buffered saline (PBS).
  • the pharmaceutically acceptable carrier comprises about 50 mM sodium phosphate in about 0.9% sodium chloride, about pH 7.4 with about 0.2% human serum albumin (HSA) in phosphate buffered saline (PBS).
  • the pharmaceutical composition is retained in the bladder of the patient for between about 30 minutes to about 2 hours. In some embodiments, the pharmaceutical composition is retained in bladder of the patient for about 30 minutes. In some embodiments, the pharmaceutical composition is retained in bladder of the patient for about 45 minutes. In some embodiments, the pharmaceutical composition is retained in bladder of the patient for about 1 hour. In some embodiments, the pharmaceutical composition is retained in bladder of the patient for about 90 minutes. In some embodiments, the pharmaceutical composition is retained in bladder of the patient for about 2 hours. In some embodiments, the instilled suspension comprising a chimeric poliovirus has sufficient contact with the whole mucosal surface of the bladder. In some embodiments, the patient is mobilized about every 15 minutes. In some embodiments, the patient is lying down and rotates between prone, supine, left lateral, and right lateral positions about every 15 minutes. In some embodiments, the pharmaceutical composition is retained in bladder of the patient for more than about 2 hours.
  • the chimeric poliovirus is administered within 7 days of a transurethral resection of a bladder tumor (TURBT). In some embodiments, the chimeric poliovirus is administered within 7 days prior to a TURBT. In some embodiments, the chimeric poliovirus is administered within 7 days following a TURBT. In some embodiments, the chimeric poliovirus is administered within about 24 hours of a TURBT. In some embodiments, the chimeric poliovirus is administered within 24 hours prior to a TURBT. In some embodiments, the chimeric poliovirus is administered within about 24 hours following a TURBT. In some embodiments, the chimeric poliovirus is lerapolturev. In some embodiments, the bladder cancer is non-muscle invasive bladder cancer (NMIBC). In some embodiments, the bladder cancer is muscle invasive bladder cancer (MIBC).
  • NMIBC muscle invasive bladder cancer
  • a method of treating a human subject having bladder cancer comprising a single administration of an effective amount of a chimeric poliovirus intravesical instillation, wherein the chimeric poliovirus is administered within 24 hours of transurethral resection of the bladder tumor (TURBT).
  • the chimeric poliovirus is administered within 24 hours prior to a TURBT.
  • the chimeric poliovirus is administered within about 24 hours following a TURBT.
  • the chimeric poliovirus is lerapolturev.
  • the bladder cancer is non-muscle invasive bladder cancer (NMIBC).
  • the bladder cancer is muscle invasive bladder cancer (MIBC).
  • the chimeric poliovirus can be lerapolturev, also known as PVSRIPO.
  • the nucleic acid sequence of lerapolturev is provided in SEQ ID NO: 1.
  • the chimeric poliovirus administered according to the methods provided herein comprises a nucleic acid sequence of SEQ ID NO: 1, or a nucleic acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto.
  • a method of treating a human subject having bladder cancer wherein the treatment comprises an induction phase, the induction phase comprising a 6- week treatment cycle comprising administering to the patient an effective amount of a chimeric poliovirus by intravesical instillation on the first day of each week.
  • the induction cycle is repeated two or more times.
  • the treatment cycle is repeated two times.
  • the treatment cycle is repeated at least 2 times, at least 3 times, at least 4 times, or up to 5 times.
  • the method is administered until disease progression or death.
  • the bladder cancer is non-muscle invasive bladder cancer (NMIBC).
  • the bladder cancer is muscle invasive bladder cancer (MIBC).
  • the induction phase comprises 4-week treatment cycles comprising administering to the patient an effective amount of a chimeric poliovirus by intravesical instillation on the first day of each cycle.
  • the 4-week treatment cycle is repeated 2, 3, 4, or more than 4 times.
  • the method is administered until disease progression or death.
  • the bladder cancer is non-muscle invasive bladder cancer (NMIBC).
  • the bladder cancer is muscle invasive bladder cancer (MIBC).
  • a method of treating a human subject having bladder cancer wherein the treatment comprises an induction phase, the induction phase comprising two 6-week treatment cycles, wherein each 6-week treatment cycle comprises administering to the patient an effective amount of a chimeric poliovirus by intravesical instillation on the first day of each week.
  • the bladder cancer is non-muscle invasive bladder cancer (NMIBC).
  • NMIBC non-muscle invasive bladder cancer
  • MIBC muscle invasive bladder cancer
  • a method of treating a human subject having bladder cancer wherein the treatment comprises an induction phase and a maintenance phase, the induction phase comprising a 6-week treatment cycle comprising administering to the patient an effective amount of a chimeric poliovirus by intravesical instillation on the first day of each week and the maintenance phase comprising 3 -week treatment cycles starting at the beginning of months 3, 6, 12, 18, 24, 30, and 36 following the start of the induction phase, each 3 -week treatment cycle comprising administering to the patient an effective amount of a chimeric poliovirus by intravesical instillation on the first day of each week, and, wherein the maintenance phase is administered following the cessation of the induction phase.
  • a method of treating a human subject having bladder cancer wherein the treatment comprises an induction phase and a maintenance phase, the induction phase comprising 4-week induction cycles comprising administering to the patient an effective amount of a chimeric poliovirus by intravesical instillation on the first day of each cycle, wherein the cycle is repeated three times, and the maintenance phase comprising 3 -week treatment cycles starting at the beginning of months 3, 6, 12, 18, 24, 30, and 36 following the start of the induction phase, each 3-week treatment cycle comprising administering to the patient an effective amount of a chimeric poliovirus by intravesical instillation on the first day of each week, and, wherein the maintenance phase is administered following the cessation of the induction phase.
  • the bladder cancer for treatment is selected from a non-muscle invasive bladder cancer (NMIBC) or a muscle invasive bladder cancer (MIBC).
  • NMIBC muscle invasive bladder cancer
  • the bladder cancer is a non-muscle invasive bladder cancer (NMIBC).
  • the NMIBC is selected from Bacillus-Calmette-Guerin (BCG)-unresponsive, high-risk NMIBC with carcinoma in situ (CIS) with papillary tumors in a patient is ineligible for cystectomy, Bacillus-Calmette-Guerin (BCG)-unresponsive, high-risk NMIBC with carcinoma in situ (CIS) with papillary tumors in a patient who has elected not to undergo cystectomy, Bacillus- Calmette-Guerin (BCG)-unresponsive, high-risk NMIBC with carcinoma in situ (CIS) without papillary tumors in a patient is ineligible for cystectomy, or Bacillus-Calmette-Guerin (BCG)- unresponsive, high-risk NMIBC with carcinoma in situ (CIS) without papillary tumors in a patient who has elected not to undergo cystectomy
  • the MIBC is selected from resectable cisplatin-ineligible/refusal MIBC, or locally advanced or metastatic bladder cancer that has not
  • the subject has refused or is ineligible for cisplatin-based therapy with glomerular filtration rate (GFR) ⁇ 60 mL/min calculated per institutional standard. In some embodiments, the subject has refused or is ineligible for cisplatin-based therapy with Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 Grade > 2 hearing loss. In some embodiments, the subject has refused or is ineligible for cisplatin-based therapy with CTCAE v 5.0 Grade > 2 peripheral neuropathy. In some embodiments, the subject previously received cancer therapy. In some embodiments, the subject previously received cancer therapy. In some embodiments, the previously received cancer therapy. In some embodiments, the previously received cancer therapy is selected from exposure to an intravesical agent, a radiation therapy, a chemotherapeutic agent, an immune checkpoint inhibitor (ICI), or a combination thereof.
  • GFR glomerular filtration rate
  • CTCAE Common Terminology Criteria for Adverse Events
  • a subject prior to administration of the first dose of the chimeric poliovirus, a subject is first administered a boost immunization of a poliovirus vaccine, for example, at least 1 week, but less than 6 weeks, prior to day 1 of the first induction phase cycle.
  • a boost immunization of a poliovirus vaccine for example, at least 1 week, but less than 6 weeks, prior to day 1 of the first induction phase cycle.
  • Suitable poliovirus vaccines for administration prior to the initiation of the induction phase include trivalent IPOL® (Sanofi-Pasteur SA).
  • the method further comprises administering an adjuvant with the chimeric poliovirus.
  • the adjuvant comprises a detergent.
  • the detergent comprises N-dodecyl-P-D-maltoside (DDM).
  • the detergent comprises Tween-80.
  • the detergent comprises SIM3.
  • the administration of detergent increases cellular viral intake.
  • the detergent is administered one or more times as a pre-wash.
  • the detergent is administered with a chimeric poliovirus by intravesical administration.
  • the pharmaceutical composition described herein further comprises detergent.
  • the detergent is administered by intravesical instillation in a solution at a concentration between at about 0.1% and at about 1.0%. In some embodiments, the detergent is administered by intravesical instillation in a solution at a concentration of at about 0.1%. In some embodiments, the detergent is administered by intravesical instillation in a solution at a concentration of at about 0.5%. In some embodiments, the detergent is administered by intravesical instillation in a solution at a concentration of at about 1.0%. In some embodiments, the detergent is administered at a concentration of from about 2% to about 6%. In some embodiments, the detergent is administered at a concentration of about 5%.
  • the chimeric poliovirus is administered via intravesical instillation following a pre-wash sequence.
  • the pre-wash sequence may increase or enhance the transduction of the chimeric poliovirus.
  • the pre-wash results in the disruption of the polyanionic glycosaminoglycan (GAG) layer overlaying the epithelium.
  • the pre-wash comprises a surfactant that disrupts the GAG layer, thereby providing access to the underlying epithelium of the bladder.
  • the surfactant is a mild polar surfactant.
  • the surfactant may be, but is not limited to, Tween-80, sodium dodecyl sulfate, or cetylpyridinium chloride.
  • the pre-wash comprises a calcium ion chelator that disrupts the GAG layer, thereby providing access to the underlying epithelium of the bladder.
  • the calcium ion chelator may be, for example, polycarbophil.
  • the pre-wash sequence comprises one or more n-dodecyl-B-D- maltoside (DDM) washes and one or more saline washes.
  • DDM n-dodecyl-B-D- maltoside
  • the DDM prewash comprises between about 0.5% and about 10% DDM.
  • the pre-wash comprises between about 2% and about 6% of DDM.
  • the pre-wash comprises about 5% DDM.
  • a saline wash is administered prior to the DDM wash.
  • a saline wash is administered after the DDM wash.
  • a saline wash is administered prior to the DDM wash and then again after the saline wash.
  • the saline wash is administered and retained within the bladder for from about 2 minutes to about 10 minutes. In some embodiments, the saline wash is administered and retained within the bladder for about 5 minutes. In some embodiments, the DDM wash is administered and retained within the bladder from about 2 minutes to about 25 minutes. In some embodiments, the DDM wash is administered and retained within the bladder for from about 10 minutes to about 20 minutes. In some embodiments, the DDM wash is administered and retained in the bladder for about 15 minutes +/- about 5 minutes. In some embodiments, the DDM wash is administered and retained in the bladder for about 5 minutes.
  • the patient prior to the administration of the chimeric poliovirus via intravesical instillation, is administered a pre-wash sequence in the order comprising i) a first wash comprising about 100 ml saline, ii) a second wash comprising about 75 ml 5% DDM, iii) a third wash comprising about 100 ml saline.
  • the patient prior to the administration of the chimeric poliovirus via intravesical instillation, is administered a pre-wash sequence in the order comprising i) a first wash comprising about 100 ml saline, ii) a second wash comprising about 75 ml 5% DDM, iii) a third wash comprising about 100 ml saline, wherein each saline wash is administered and retained in the bladder for about 5 minutes and the DDM wash is administered and retained in the bladder for about 15 minutes +/- about 5 minutes.
  • the chimeric poliovirus is further administered in combination with an ICI.
  • the improved treatment methods described herein block tumor infiltrating immune effector cell immune checkpoint expression downregulation to prevent tumor immune escape, resulting in an extended or prolonged efficacy of an anti-cancer regimen.
  • the administration of an effective amount of a chimeric poliovirus and an effective amount of an ICI are capable of synergizing to reverse and/or significantly delay the growth of tumors and/or the development of ICI therapy resistance.
  • Suitable ICIs for use in the methods described herein include, but are not limited to, a programmed cell death- 1 (PD-1) inhibitor, a programmed cell death -ligand 1 (PD-L1) inhibitor, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, a lymphocyteactivation gene 3 (LAG-3) inhibitor, a T-cell immunoglobulin mucin-3 (TIM-3) inhibitor, a T cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitor, a programmed cell death-ligand 2 (PD-L2) inhibitor, a V-domain Ig suppressor of T-cell activation (VISTA) inhibitor, a B7- H3/CD276 inhibitor, an indoleamine 2, 3 -dioxygenase (IDO) inhibitor, a killer immunoglobulin- like receptor (KIR) inhibitor, a carcinoembryonic antigen cell adhesion molecule (CEACAM) inhibitor against molecules such as CEACAM-1, CEACAM
  • the improved treatment methods described herein provide enhanced therapeutic efficacy through the regulation of T cells, including activation of cytotoxic CD8+ T-cell function and maturation into memory CD8+ T-cells.
  • the improved treatment methods described herein that combine administration of a chimeric poliovirus construct at certain doses and interval frequencies in combination with administering an effective amount of an ICI at certain doses and interval frequencies provide anti-tumor potency and measurable reductions in tumor progression.
  • the ICI is administered at the standard recommended dose and schedule as described on its FDA approved label.
  • the method further comprises administering an anti -cancer therapy selected from an intravesical agent, a radiation therapy, a chemotherapeutic agent, or a combination thereof.
  • the chimeric poliovirus can be administered intratumorally between induction or maintenance phase treatment cycles.
  • described herein is a method of treating a human subject having bladder cancer, wherein the treatment comprises an induction phase, the induction phase comprising a 6-week cycle comprising administering intratumorally to the patient an effective amount of a chimeric poliovirus on the first day of each week.
  • described herein is a method of treating a human subject having bladder cancer, wherein the treatment comprises an induction phase, the induction phase comprising two 6-week cycles, each 6-week cycle comprising administering intratumorally to the patient an effective amount of a chimeric poliovirus on the first day of each week.
  • described herein is a method of treating a human subject having bladder cancer, wherein the treatment comprises an induction phase and a maintenance phase, the induction phase comprising a 6-week cycle comprising administering intratumorally to the patient an effective amount of a chimeric poliovirus on the first day of each week the maintenance phase comprising 3-week cycles starting at the beginning of months 3, 6, 12, 18, 24, 30, and 36 following the start of the induction phase, each 3-week cycle comprising administering intratumorally to the patient an effective amount of a chimeric poliovirus on the first day of each week, and, wherein the maintenance phase is administered following the cessation of the induction phase.
  • the induction phase comprising a 6-week cycle comprising administering intratumorally to the patient an effective amount of a chimeric poliovirus on the first day of each week
  • the maintenance phase comprising 3-week cycles starting at the beginning of months 3, 6, 12, 18, 24, 30, and 36 following the start of the induction phase, each 3-week cycle comprising administering intratumorally to the patient an
  • described herein is a method of treating a human subject having bladder cancer, wherein the treatment comprises an induction phase and a maintenance phase, the induction phase comprising a 6-week cycle comprising administering intratumorally to the subject an effective amount of a chimeric poliovirus on the first day of each week, the maintenance phase comprising 1-week cycles starting at the beginning of months 3, 6, 12, 18, 24, 30, and 36 following the start of the induction phase, each 1-week cycle comprising administering intratumorally to the subject an effective amount of a chimeric poliovirus on the first day of each week, and, wherein the maintenance phase is administered following the cessation of the induction phase.
  • the induction phase comprising a 6-week cycle comprising administering intratumorally to the subject an effective amount of a chimeric poliovirus on the first day of each week
  • the maintenance phase comprising 1-week cycles starting at the beginning of months 3, 6, 12, 18, 24, 30, and 36 following the start of the induction phase
  • each 1-week cycle comprising administering intratumorally to the
  • the chimeric poliovirus is administered within 7 days of a TURBT.
  • the induction phase is repeated one or more times.
  • the maintenance phase follows immediately after the induction phase.
  • the methods described herein can be used to treat a solid bladder tumor comprising administering the chimeric poliovirus to between 1 and 10 lesions.
  • the chimeric poliovirus is administered to at least 1 lesion, at least 2 lesions, at least 3 lesions, at least 4 lesions, at least 5 lesions, at least 6 lesions, at least 7 lesions, at least 8 lesions, at least 9 lesions, or up to 10 lesions per administration.
  • the administration of a treatment protocol described herein may provide enhanced antitumor efficacy in patients.
  • the administration of a treatment protocol described herein provides improved progression free survival (PFS) and/or overall survival (OS) compared to a patient receiving cystectomy or TURBT alone.
  • PFS progression free survival
  • OS overall survival
  • an improvement in PFS is observed.
  • an improvement in OS is observed.
  • the methods described herein reduce recurrence rate of bladder tumor formation. In some embodiments, the methods described herein decrease the need of bladder tumor removal surgeries selected from transurethral resection of the bladder tumor (TURBT) or cystectomy. In some embodiments, the methods described herein decrease the frequency of TURBT. In some embodiments, the methods described herein decrease the frequency of cystectomy.
  • FIG. 1A - E shows that chemical conditions do not significantly alter lerapolturev infectivity and immunomodulation.
  • the U87 cell death assay was conducted at multiplicity of infection values (MOI) of 20, 6, and 2.2 tested in triplicate.
  • FIG. 1A The effect of a 2-hour incubation of cells with Tween-80 on lerapolturev infectivity was analyzed using the U87 Potency Assay.
  • the y-axis represents the Absorbance value of each experimental group, while the x-axis represents the experimental conditions in different MOI groups. Concentration of Tween-80 ranged from 0.1% - 1.0%.
  • FIG. IB The effect of a 2-hour incubation of cells with n-dodecyl-B-D-maltoside (DDM) on lerapolturev infectivity was analyzed using the U87 Potency Assay.
  • the y-axis represents the Absorbance value of each experimental group, while the x-axis represents the experimental conditions in different MOI groups. Concentration of DDM ranged from 0.1% - 1.0%.
  • FIG. 1C The effect of a 2-hour incubation of cells with varying media pH conditions on lerapolturev infectivity was analyzed using the U87 Potency Assay.
  • the y-axis represents the Absorbance value of each experimental group, while the x-axis represents the experimental conditions in different MOI groups. pH values were 3, 7, and 10.
  • FIG. ID The effect of a 2-hour incubation of cells with urine on lerapolturev infectivity was analyzed using the U87 Potency Assay.
  • the y-axis represents the Absorbance value of each experimental group, while the x-axis represents the experimental conditions in different MOI groups. Concentration of urine ranged from 11% - 100%.
  • FIG. IE The effect of a 2-hour incubation of cells with saliva on lerapolturev infectivity was analyzed using the U87 Potency Assay.
  • the y-axis represents the Absorbance value of each experimental group, while the x-axis represents the experimental conditions in different MOI groups. Concentration of saliva ranged from 11% - 100%.
  • FIG.2A - E shows that chemical conditions do not significantly dampen levels of interferon beta (IFN- P) secreted from cells infected with lerapolturev as measured by ELISA.
  • FIG. 2A is a bar plot showing the effect of varying concentration of detergent Tween-80 on the levels of IFN-P secreted by infected cells as measured by ELISA.
  • the y-axis represents the amount of secreted IFN-P in picograms/milliliter (pg/mL), while the x-axis represents the different experimental groups.
  • Different multiplicity of infection (MOI) values (2, 6.6, 20) and experimental groups (GM-PC, Tween-80 0.1%, 0.5%, 1.0%) are also illustrated above the graph for ease of viewing.
  • GM Growth Media.
  • FIG. 2B is a bar plot showing the effect of varying concentration of detergent n-dodecyl- B-D-maltoside (DDM) on the levels of IFN-P secreted by infected cells as measured by ELISA.
  • the y-axis represents the amount of secreted IFN-P in picograms/milliliter (pg/mL), while the x- axis represents the different experimental groups.
  • Different multiplicity of infection (MOI) values (2, 6.6, 20) and experimental groups (GM-PC, DDM 0.1%, 0.5%, 1.0%) are also illustrated above the graph for ease of viewing.
  • FIG. 2C is a bar plot showing the effect of varying concentration of Urine on the levels of IFN-P secreted by infected cells as measured by ELISA.
  • the y-axis represents the amount of secreted IFN-P in picograms/milliliter (pg/mL), while the x-axis represents the different experimental groups.
  • Different multiplicity of infection (MOI) values (2, 6.6, 20) and experimental groups (GM-PC, Urine 11%, 37%, 56%, 100%) are also illustrated above the graph for ease of viewing.
  • FIG. 2D is a bar plot showing the effect of varying concentration of urine on the levels of IFN-P secreted by infected cells as measured by ELISA.
  • the y-axis represents the amount of secreted IFN-P in picograms/milliliter (pg/mL), while the x-axis represents the different experimental groups.
  • Different multiplicity of infection (MOI) values (2, 6.6, 20) and experimental groups (GM-PC, Urine 11%, 37%, 56%, 100%) are also illustrated above the graph for ease of viewing.
  • FIG. 2E is a bar plot showing the effect of varying concentration of Saliva on the levels of IFN-P secreted by infected cells as measured by ELISA.
  • the y-axis represents the amount of secreted IFN-P in picograms/milliliter (pg/mL), while the x-axis represents the different experimental groups.
  • Different multiplicity of infection (MOI) values (2, 6.6, 20) and experimental groups (GM-PC, Saliva 11%, 37%, 56%, 100%) are also illustrated above the graph for ease of viewing.
  • FIG. 3 A - C shows that a minimum of 30 minutes of lerapolturev contact of cells is feasible for successful lerapolturev infection.
  • FIG. 3A is a diagram illustrating the experimental design showing the timeline of lerapolturev incubation time lengths.
  • the x-axis represents the time length of the experiment, totaling 44 hours.
  • the y-axis represents different experimental groups with different time lengths of lerapolturev cell contact, ranging from no time (neg control) to 44 hours (pos control).
  • Black arrows represent the lengths of time lerapolturev is contacting cells
  • white arrows represent the lengths of time fresh media (absent lerapolturev) is contacting cells in each experimental condition.
  • FIG. 3B is a bar plot showing the effect of varying the length of lerapolturev incubation on lerapolturev cell infectivity was analyzed using the U87 Potency Assay.
  • the y-axis represents the Absorbance value of each experimental group, while the x-axis represents the experimental conditions in different multiplicity of infection groups.
  • FIG. 3C is a bar plot showing the effect of varying lengths of lerapolturev contact time on the levels of IFN-P secreted by infected cells as measured by ELISA.
  • the y-axis represents the amount of secreted IFN-P in picograms/milliliter (pg/mL), while the x-axis represents the different experimental groups.
  • MOI multiplicity of infection.
  • FIG. 4 is a flow chart diagram showing the dose confirmation scheme to identify the exemplary dose of lerapolturev to be administered in a proposed clinical trial.
  • the exemplary dose of lerapolturev to be administered by intravesical instillation will be determined using a 3+3 dose escalation approach. Three patients initially treated with a dose of 2.0xl0 9 TCID50 and the frequency of dose limiting toxicity events will be assessed. The decision to escalate or de-escalate the lerapolturev dose will be determined by the number of DLTs observed during the initial 14 days following administration of lerapolturev as advised by the Data Safety Monitoring Committee (DSMC).
  • DSMC Data Safety Monitoring Committee
  • MTD maximally tolerated dose
  • FIG. 5A - D show exemplary intravesical instillation administration schedules of a chimeric poliovirus as provided herein.
  • FIG. 5A is an exemplary chimeric poliovirus administration schedule comprising an induction (I) phase lasting one six-week Induction cycle (IC1).
  • a chimeric poliovirus e.g., lerapolturev
  • I induction
  • IC1 six-week Induction cycle
  • FIG. 5B is an exemplary chimeric poliovirus administration schedule comprising an induction (I) phase lasting two separate six-week Induction cycles (IC1 + IC2).
  • a chimeric poliovirus e.g., lerapolturev
  • IC1 + IC2 six-week Induction cycles
  • FIG. 5C is an exemplary chimeric poliovirus administration schedule comprising an induction (I) phase and a maintenance (M) phase.
  • a chimeric poliovirus e.g., lerapolturev
  • M phase begins, in which a chimeric poliovirus (e.g., lerapolturev) is to be administered on the first day of each of the first three weeks of months 3, 6, 12, 18, 24, 30, and 36.
  • Fig. 5D is an exemplary chimeric poliovirus administration schedule comprising an induction (I) phase and an alternate maintenance (M) phase.
  • a chimeric poliovirus e.g., lerapolturev
  • M phase begins, in which a chimeric poliovirus (e.g., lerapolturev) is to be administered on the first day of the first week of months 3, 6, 12, 18, 24, 30, and 36.
  • the present invention provides methods for treating a human patient having a cancer or which are unresponsive to previous therapy.
  • multiple administrations of a chimeric poliovirus can be administered by intravesical instillation or at another suitable delivery area to a patient having a bladder cancer and/or one or more disease or disorders associated with bladder tumors or which are unresponsive to previous therapy.
  • the “patient” or “subject” or “participant” treated is typically a human patient, although it is to be understood the methods described herein are effective with respect to other animals, such as mammals. More particularly, the term patient can include animals used in assays such as those used in preclinical testing including but not limited to mice, rats, monkeys, dogs, pigs, and rabbits; as well as domesticated swine (pigs and hogs), ruminants, equine, poultry, felines, bovines, murines, canines, and the like.
  • An “effective amount” as used herein, means an amount which provides a therapeutic or prophylactic benefit.
  • a disease as the term is used herein, means to reduce the frequency or severity of at least one sign or symptom of a disease, disorder, or side-effect experienced by a patient (i.e., palliative treatment) or to decrease a cause or effect of the disease, disorder (i.e., disease -modifying treatment), or side effect experienced by a patient as a result of the administration of a therapeutic agent.
  • detergent means a surfactant or mixture of surfactants with amphiphilic structures, wherein each molecule has a hydrophilic (polar) head and a long hydrophobic (non-polar) tail
  • response evaluation criteria in solid tumors version 1.1 refers to a revised guideline that describes a standard approach to solid tumor measurements and definitions for objective change in tumor size for use in trials in which an immunotherapy is used (Eisenhauer et al. Eur J Cancer.45:228-47(2009)).
  • iRECIST refers to a consensus guideline that describes a standard approach to solid tumor measurements and definitions for objective change in tumor size for use in trials in which an immunotherapy is used (Seymour et al. Lancet Oncol. 18(3):30074- 8(2019)).
  • CR complete response
  • partial response refers to greater than or equal to 30% decrease in the sum of the longest diameters of target lesions compared with baseline per RECIST 1.1.
  • PD progressive disease
  • stable disease refers to neither PR or PD occurring when evaluating target lesions per RECIST 1.1.
  • all survival refers to the time from treatment group assignment until death from any cause.
  • DOR duration of response
  • DCR disease control rate
  • DCR-6mo Disease control rate-6months
  • durable response rate refers to the proportion of patients with confirmed CR or PR (per RECIST 1.1) last at least 6 months.
  • progression-free survival refers to the time (i.e., number of months) from treatment group assignment until date of documented radiologic disease progression per RECIST 1.1 or death due to any cause, whichever comes first.
  • percent identical when used in the context of nucleic acid sequences refers to the residues in the two sequences being compared which are the same when aligned for maximum correspondence.
  • the length of sequence identity comparison may be over the full-length of the sequence, or, or alternatively a fragment of at least about 50 to 2500 nucleotides.
  • percent identical may be readily determined for amino acid sequences, over the full-length of a protein, or a fragment thereof.
  • a fragment is at least about 8 amino acids in length and may be up to about 7500 amino acids. Examples of suitable fragments are described herein.
  • aligned sequences refer to multiple nucleic acid sequences or protein (amino acids) sequences, often containing corrections for missing or additional bases or amino acids as compared to a reference sequence. Alignments can be performed using any of a variety of publicly or commercially available Multiple Sequence Alignment Programs. Examples of such programs include, “Clustal Omega”, “Clustal W”, “CAP Sequence Assembly”, “MAP”, and “MEME”, which are accessible through Web Servers on the internet. Other sources for such programs are known to those of skill in the art. Alternatively, Vector NTI utilities are also used.
  • nucleotide sequence identity there are also a number of algorithms known in the art that can be used to measure nucleotide sequence identity, including those contained in the programs described above.
  • polynucleotide sequences can be compared using FastaTM, a program in GCG Version 6.1.
  • FastaTM provides alignments and percent sequence identity of the regions of the best overlap between the query and search sequences.
  • percent sequence identity between nucleic acid sequences can be determined using FastaTM with its default parameters (a word size of 6 and the NOPAM factor for the scoring matrix) as provided in GCG Version 6.1, herein incorporated by reference.
  • sequence alignment programs are also available for amino acid sequences, e.g., the “Clustal Omega”, “Clustal X”, “MAP”, “PIMA”, “MSA”, “BLOCKMAKER”, “MEME”, and “Match-Box” programs. Generally, any of these programs are used at default settings, although one of skill in the art can alter these settings as needed. Alternatively, one of skill in the art can utilize another algorithm or computer program which provides at least the level of identity or alignment as that provided by the referenced algorithms and programs. See, e.g., J. D. Thomson et al, Nucl. Acids. Res., “A comprehensive comparison of multiple sequence alignments”, 27(13):2682-2690 (1999).
  • chimeric poliovirus is a modified serotype 1 live attenuated (SabinTM) PV vaccine (PV1S) with the cognate internal ribosome entry site (IRES) replaced with that of human rhinovirus type 2 (HRV2), for example lerapolturev, also known as PVSRIPO.
  • SabinTM modified serotype 1 live attenuated
  • IVS internal ribosome entry site
  • HRV2 human rhinovirus type 2
  • lerapolturev also known as PVSRIPO.
  • the nucleic acid sequence of lerapolturev is provided in Table 2 (SEQ ID NO: 1).
  • Lerapolturev is a recombinant rhinovirus/poliovirus chimera developed to treat patients with solid tumor cancers.
  • the foreign IRES of PVSRIPO causes neuronal incompetence: a failure to recruit host ribosomes, translate viral genomes, and propagate in neurons, each of which contribute to the ablation of neurovirulence and absence of polio-related neurologic injury (Dobrikova et al. J Virol. 86(5):2750-9(2012)).
  • Lerapolturev exhibits selective infectivity and cytotoxicity towards CD155-expressing cells, which includes malignant cells of virtually all solid tumors (Luo et al. Front Oncol. 11 :660273(2021); Takai et al. Nat Rev Mol Cell Biol. 9:603- 15(2008); Chandramohan et al. Arch Pathol Lab Med. 141(12): 1697-1704(2017); Liu et al.
  • CD 155 -expressing solid tumors are cancers of the bladder, including both muscle invasive bladder cancer (MIBC) and non-muscle invasive bladder cancer (NMIBC).
  • MIBC muscle invasive bladder cancer
  • NMIBC non-muscle invasive bladder cancer
  • Lerapolturev/PVSRIPO Sequence Lerapolturev has tropism towards major components of the tumor and tumor microenvironment (TME), capable of infecting and promoting cytotoxicity of not only tumor cells, but of CD155-expressing infiltrating monocytes, macrophages, and dendritic cells (Freistadt et al. Virology. 195:798-803(1993)).
  • TEE tumor and tumor microenvironment
  • Malignant cells of virtually all solid tumors, including bladder tumors exhibit increased CD155 receptor expression (Luo et al. Front Oncol. 11:660273(2021); Takai et al. Nat Rev Mol Cell Biol. 9:603-15(2008); Chandramohan et al. Arch Pathol Lab Med.
  • bladder cancer tumors demonstrate significantly upregulated CD 155 expression which was found to be associated with poorer survival probability in human patients (Luo et al. Front Oncol. 11 :660273(2021)).
  • Bladder tumors with high CD155 expression also had significantly increased CD8+ T cell, neutrophil, macrophage, and dendritic cell tumor infiltration when compared with low CD155 expressing tumors (Luo et al. Front Oncol. 11 :660273(2021)). While the presence of CD155 is sufficient for lerapolturev cell entry, it is not absolutely required for PVSRIPO replication.
  • lerapolturev infects antigen presenting cells (APCs)/dendritic cells (DCs) leading to the upregulation of antigen presentation (Brown et al. Science Translational Medicine. 9(408)(2017)) and the triggering of Type 1 interferon (IFN) inflammation in the TME (Brown et al. Science Translational Medicine. 9(408)(2017)).
  • APCs antigen presenting cells
  • DCs dendritic cells
  • IFN Type 1 interferon
  • the bladder cancer is a resectable cisplatin-ineligible/refusal muscle invasive bladder cancer (MIBC).
  • MIBC muscle invasive bladder cancer
  • the bladder cancer is a locally advanced or metastatic bladder cancer that has not progressed with first-line platinum-containing chemotherapy.
  • the bladder cancer is a Bacillus-Calmette-Guerin (BCG)- unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.
  • BCG Bacillus-Calmette-Guerin
  • NMIBC non-muscle invasive bladder cancer
  • CIS carcinoma in situ
  • the bladder cancer is a carcinoma in situ (CIS) of the urinary bladder.
  • the bladder cancer is a primary or recurrent stage Ta and/or T1 papillary bladder cancer tumors following transurethral resection (TUR).
  • the human patient is an adult with a low risk of disease recurrence and progression.
  • the human patient is an adult with a high risk of disease recurrence and progression.
  • the bladder cancer is a bladder cancer previously treated with PD-1 and/or PD-L1 inhibitor therapy.
  • the bladder cancer is selected from a non-muscle invasive bladder cancer (NMIBC) or a muscle invasive bladder cancer (MIBC).
  • NMIBC non-muscle invasive bladder cancer
  • MIBC muscle invasive bladder cancer
  • the patient has prior history of stage Ta, Tl, or Tis urothelial carcinoma of the bladder.
  • the bladder tumors are comprised of up to 50% squamous or glandular differentiation.
  • the patient has documented tumor recurrence at cystoscopy where the bladder tumor is amenable to TURBT or cystectomy.
  • the patient has no history of variant bladder histologies selected from sarcomatoid, plasmacytoid, small cell or neuroendocrine, pure squamous cell carcinoma, pure adenocarcinoma, micropapillary, nested, lymphepithelioma-like, clear cell, or combinations thereof.
  • the patient has a history of variant bladder histologies selected from sarcomatoid, plasmacytoid, small cell or neuroendocrine, pure squamous cell carcinoma, pure adenocarcinoma, micropapillary, nested, lymphepithelioma-like, clear cell, or combinations thereof.
  • the patient has a measured or calculated (per institutional standard) creatinine clearance > 30 ml/min. In some embodiments, the patient has a measured or calculated (per institutional standard) creatinine clearance > 45 ml/min. In some embodiments, the patient has a GFR ⁇ 60 mL/min calculated per institutional standard. In some embodiments, the patient has a formalin-fixed paraffin-embedded tumor specimen with an associated pathology report documenting NMIBC. In some embodiments, the patient harbors bladder tumor lesions amenable to intratumoral injection. In some embodiments, the patient was previously exposed to intravesical agents selected from Bacillus Calmette-Guerin (BCG), mitomycin C, epirubicin, oncolytic viruses, investigational therapies.
  • BCG Bacillus Calmette-Guerin
  • the patient received no prior radiation to the pelvis. In some embodiments, the patient received prior radiation to the pelvis. In some embodiments, the patient received prior systemic therapy for bladder cancer. In some embodiments, the systemic therapy comprised administration of a PD-1/ PD-L1 inhibitor. In some embodiments, the patient has no history of vesicoureteric reflux or an indwelling urinary stent. In some embodiments, the patient has a history of vesicoureteric reflux or an indwelling urinary stent. In some embodiments, the patient has a history of stage T2 or higher bladder cancer. In some embodiments, the patient has no history of stage T2 or higher bladder cancer. In some embodiments, the patient has the ability to retain urine for 2 hours.
  • the bladder cancer is a non-muscle invasive bladder cancer (NMIBC).
  • NMIBC non-muscle invasive bladder cancer
  • the NMIBC is a Bacillus-Calmette-Guerin (BCG)- unresponsive, high-risk NMIBC with carcinoma in situ (CIS) with papillary tumors in a patient is ineligible for cystectomy.
  • the NMIBC is a Bacillus-Calmette-Guerin (BCG)-unresponsive, high-risk NMIBC with carcinoma in situ (CIS) with papillary tumors in a patient who has elected not to undergo cystectomy.
  • the NMIBC is a Bacillus-Calmette-Guerin (BCG)-unresponsive, high-risk NMIBC with carcinoma in situ (CIS) without papillary tumors in a patient is ineligible for cystectomy.
  • the NMIBC is a Bacillus-Calmette-Guerin (BCG)-unresponsive, high-risk NMIBC with carcinoma in situ (CIS) without papillary tumors in a patient who has elected not to undergo cystectomy.
  • the human patient is an adult with a high risk of disease recurrence and progression. In some embodiments, the human patient is an adult with a low risk of disease recurrence and progression.
  • the subject is an adult selected from high risk, intermediate risk, or low risk of disease recurrence and progression. In some embodiments, the subject is an adult with a low risk of disease recurrence and progression. In some embodiments, the adult with low risk of disease recurrence and progression has low grade solitary Ta ⁇ 3cm. In some embodiments, the adult with low risk of disease recurrence and progression has papillary urothelial neoplasm of low malignant potential. In some embodiments, the subject is an adult with an intermediate risk of disease recurrence and progression. In some embodiments, the adult with intermediate risk of disease recurrence and progression has low grade Ta that recurs within 1 year.
  • the adult with intermediate risk of disease recurrence and progression has solitary low grade TA > 3cm. In some embodiments, the adult with intermediate risk of disease recurrence and progression has multifocal low-grade Ta ⁇ 3cm. In some embodiments, the adult with intermediate risk of disease recurrence and progression has low grade Tl. In some embodiments, the subject is an adult with a high risk of disease recurrence and progression. In some embodiments, the adult with high risk of disease recurrence and progression has high grade Tl. In some embodiments, the adult with high risk of disease recurrence and progression has any recurrent high-grade Ta.
  • the adult with high risk of disease recurrence and progression has high grade Ta > 3cm or multifocal Ta. In some embodiments, the adult with high risk of disease recurrence and progression has any carcinoma in situ. In some embodiments, the adult with high risk of disease recurrence and progression has any BCG failure in a high-grade Ta. In some embodiments, the adult with high risk of disease recurrence and progression C has any variant histology. In some embodiments, the adult with high risk of disease recurrence and progression has any lymphovascular invasion. In some embodiments, the adult with high risk of disease recurrence and progression has any high grade prostatic urothelial involvement.
  • the bladder cancer is muscle invasive bladder cancer (MIBC).
  • MIBC muscle invasive bladder cancer
  • the MIBC is a resectable cisplatin-ineligible/refusal MIBC.
  • the MIBC is a locally advanced or metastatic bladder cancer that has not progressed with first-line platinum-containing chemotherapy.
  • the MIBC is a unresectable, locally advanced tumor.
  • the unresectable, locally advanced MIBC tumor is selected from T4b, any N, ant T, N 2-3, Ml, or combinations thereof.
  • NMIBC comprises noninvasive papillary carcinomas (Ta; 48%), submucosal invasive tumors (Tl; 27%), carcinoma in situ (CIS; 2%) or some combination of these types (Boustead et al. BJU Int. 113 (6): 924-30(2014); Chang et al. J Urol. 196(4): 1021-9(2016)); and subjects may be categorized as low-, intermediate-, or high-risk of disease recurrence and progression. In some embodiments, the subject has high risk, intermediate risk, or low risk of disease recurrence and progression, n some embodiments, the subject has a low risk of disease recurrence and progression .
  • the subject with low risk of disease recurrence and progression has low grade solitary Ta ⁇ 3cm. In some embodiments, the subject with low risk of disease recurrence and progression has papillary urothelial neoplasm of low malignant potential. In some embodiments, the subject has an intermediate risk of disease recurrence and progression. In some embodiments, the subject with intermediate risk of disease recurrence and progression has low grade Ta that recurs within 1 year. In some embodiments, the subject with intermediate risk of disease recurrence and progression has solitary low grade TA > 3cm. In some embodiments, the subject with intermediate risk of disease recurrence and progression has multifocal low-grade Ta ⁇ 3cm.
  • the subject with intermediate risk of disease recurrence and progression has low grade Tl. In some embodiments, the subject has a high risk of developing MIBC. In some embodiments, the subject with high risk of disease recurrence and progression has high grade Tl. In some embodiments, the subject with high risk of disease recurrence and progression has any recurrent high-grade Ta. In some embodiments, the subject with high risk of disease recurrence and progression has high grade Ta > 3cm or multifocal Ta. In some embodiments, the subject with high risk of disease recurrence and progression has any carcinoma in situ. In some embodiments, the subject with high risk of disease recurrence and progression has any BCG failure in a high-grade Ta.
  • the subject with high risk of disease recurrence and progression has any variant histology. In some embodiments, the subject with high risk of disease recurrence and progression has lymphovascular invasion. In some embodiments, the subject with high risk of disease recurrence and progression has high grade prostatic urothelial involvement.
  • the subject to be treated has bladder cancer and was previously treated with an immunomodulatory intravesical agent, radiation therapy, a chemotherapeutic agent, an immune checkpoint inhibitor (ICI), or a combination thereof.
  • an immunomodulatory intravesical agent radiation therapy, a chemotherapeutic agent, an immune checkpoint inhibitor (ICI), or a combination thereof.
  • ICI immune checkpoint inhibitor
  • the subject to be treated has bladder cancer and was previously treated with an immunomodulatory intravesical agent.
  • the immunomodulatory intravesical agent is selected from BCG, mitomycin C, epirubicin, or a combination thereof.
  • the immunomodulatory intravesical agent is BCG.
  • the subject is BCG-refractory.
  • the immunomodulatory intravesical agent is mitomycin C.
  • the immunomodulatory intravesical agent is epirubicin.
  • the subject to be treated has bladder cancer and was previously treated with a chemotherapeutic agent.
  • Previously administered chemotherapeutic agents include, but are not limited to, cisplatin, carboplatin, oxaliplatin, gemcitabine, doxorubicin, docetaxel, methotrexate, vinblastine, cabazitaxel, or a combination thereof.
  • the chemotherapeutic agent is a platinum-based drug.
  • the chemotherapeutic agent is one or more platinum-based drug in combination with one or more non-platinum-based drug.
  • the platinum-based drug comprises cisplatin.
  • the platinum-based drug comprises carboplatin.
  • the platinum-based drug comprises oxaliplatin.
  • the chemotherapeutic agent is gemcitabine.
  • the chemotherapeutic agent is doxorubicin.
  • the chemotherapeutic agent is docetaxel.
  • the chemotherapeutic agent is methotrexate.
  • the chemotherapeutic agent is vinblastine.
  • the chemotherapeutic agent is cabazitaxel.
  • the chemotherapeutic agent is enfortumab vedotin.
  • the subject to be treated has bladder cancer and was previously treated with radiation therapy. In some embodiments, the subject was previously treated with external -beam radiation therapy. In some embodiments, the subject was previously treated with intraoperative radiation therapy. In some embodiments, the subject was previously treated with image guided radiation therapy. In some embodiments, the subject was previously treated with intensity -modulated radiation therapy. In some embodiments, the subject was previously treated with x-ray beam radiation.
  • the subject to be treated has bladder cancer and was previously treated with an ICI.
  • the ICI is selected from a PD-1 inhibitor or a PD-L1 inhibitor.
  • the ICI is an PD-1 inhibitor.
  • the PD-1 inhibitor is selected from pembrolizumab or nivolumab.
  • the PD-1 inhibitor is pembrolizumab.
  • the PD-1 inhibitor is nivolumab.
  • the ICI is a PD-L1 inhibitor.
  • the PD-L1 inhibitor is selected from atezolizumab, durvalumab, or avelumab.
  • the PD-L1 inhibitor is atezolizumab.
  • the PD-L1 inhibitor is durvalumab.
  • the PD-L1 inhibitor is avelumab.
  • the subject to be treated has bladder cancer and was previously treated with a bladder cancer therapy selected from rogaratinib (BAY1163877), derazantinib (ARQ 087), tazemetostat (TAZVERIK®), cabozantinib (CABOMETYX®), sitravatinib (MGCD516), adenovirus, a coxsackievirus, entinostat (SNDX-275/MS-275), epacadostat (INCB24360), CYT107, bempegaldesleukin (BEMPEG/NKTR-214), urelumab (BMS-663513), lirilumab (IPH2102), enfortumab vedotin (PADCEV®), oleclumab (MEDI9447), guadecitabine (SGI- 110), olaparib (LYNPARZA®), or a combination thereof.
  • a bladder cancer therapy selected from
  • a specifically-timed administration schedule of a chimeric poliovirus by intravesical instillation provides enhanced anti -bladder tumor efficacy and reduced tumor recurrence rate.
  • a chimeric poliovirus is administered to the subject at periodic intervals for the initiation of an immune effector cell response (i.e., an induction phase).
  • the chimeric poliovirus is administered in one or more induction phases.
  • the induction phase comprises one or more treatment cycles, wherein the treatment cycle comprises one or more weeks wherein a chimeric poliovirus is administered on the first day of each week.
  • the method is administered until disease progression or death.
  • the chimeric poliovirus comprises lerapolturev (also known as PVSRIPO).
  • the treatment cycle lasts 1-week, 2-weeks, 3-weeks,
  • each treatment cycle lasts 6-weeks. In some embodiments, each treatment cycle lasts 4-weeks.
  • the induction phase is administered alone. In some embodiments, the induction phase is followed by a maintenance phase.
  • a method of treating a human subject having bladder cancer wherein the treatment comprises an induction phase, the induction phase comprising one or more 6-week treatment cycles, wherein the one or more 6-week treatment cycles comprise administering to the patient an effective amount of a chimeric poliovirus by intravesical instillation on the first day of each week.
  • the chimeric poliovirus comprises lerapolturev.
  • the treatment cycle lasts 1-week, 2-weeks, 3-weeks, 4-weeks,
  • each of the one or more treatment cycles are administered 1-week, 2-weeks, 3-weeks, 4-weeks, 5 weeks, 6- weeks, 3 -months, 6-months, or greater from each other.
  • the induction cycle is repeated if no objective response rate (ORR) is exhibited by the patient.
  • ORR objective response rate
  • the induction cycle is repeated if no complete response (CR) is exhibited by the patient.
  • the induction cycle is repeated if no partial response (PR) is exhibited by the patient.
  • the induction phase comprises 2 or more treatment cycles, for example, 2, 3, 4, or more than 5 treatment cycles.
  • the induction phase comprises between 2 and 5 treatment cycles. In some embodiments, the induction phase comprises at least 2, at least 3, at least 4, or 5 or more treatment cycles. In some embodiments, the induction phase is administered alone. In some embodiments, the induction phase is followed by a maintenance phase.
  • a method of treating a human subject having bladder cancer comprising a single administration of an effective amount of a chimeric poliovirus intravesical instillation, wherein the chimeric poliovirus is administered within 24 hours of transurethral resection of the bladder tumor (TURBT).
  • the chimeric poliovirus is administered within 24 hours prior to a TURBT.
  • the chimeric poliovirus is administered within about 24 hours following a TURBT.
  • the chimeric poliovirus is lerapolturev.
  • the bladder cancer is non-muscle invasive bladder cancer (NMIBC).
  • the bladder cancer is muscle invasive bladder cancer (MIBC).
  • a method of treating a human subject having bladder cancer wherein the treatment comprises an induction phase, the induction phase comprising two 6-week treatment cycles, wherein each 6-week treatment cycle comprises administering to the patient an effective amount of a chimeric poliovirus by intravesical instillation on the first day of each week.
  • the chimeric poliovirus comprises lerapolturev.
  • the two 6-week treatment cycles are administered 1-week, 2-weeks, 3-weeks, 4- weeks, 5 weeks, 6-weeks, 3-months, 6-months, or greater from each other.
  • the induction phase is administered alone.
  • the induction phase is followed by a maintenance phase.
  • the induction phase comprises one or more 4-week treatment cycles comprising administering to the patient an effective amount of a chimeric poliovirus by intravesical instillation on the first day of each cycle.
  • the method is administered until disease progression or death.
  • the chimeric poliovirus comprises lerapolturev.
  • each of the one or more treatment cycles are administered 1-week, 2-weeks, 3-weeks, 4-weeks, 5 weeks, 6-weeks, 3-months, 6-months, or greater from each other.
  • the induction phase is administered alone.
  • the induction phase is followed by a maintenance phase.
  • the induction phase is administered alone.
  • the induction phase is followed by a maintenance phase.
  • the induction phase comprises 4-week treatment cycles comprising administering to the patient an effective amount of a chimeric poliovirus by intravesical instillation on the first day of each cycle, wherein the 4-week treatment cycle is repeated three times.
  • the chimeric poliovirus comprises lerapolturev.
  • each of the one or more treatment cycles are administered 1-week, 2-weeks, 3-weeks, 4-weeks, 5 weeks, 6- weeks, 3-months, 6-months, or greater from each other.
  • the induction phase is administered alone.
  • the induction phase is followed by a maintenance phase.
  • a chimeric poliovirus is administered to the subject at periodic intervals for the maintenance of the immune effector cell response (i.e., a maintenance phase).
  • the chimeric poliovirus is administered in one or more maintenance phases.
  • the maintenance phase is administered following an objective response rate (ORR) exhibited by the patient following the cessation of the induction phase.
  • the maintenance phase is administered following a complete response (CR) exhibited by the patient following the cessation of the induction phase.
  • the method is administered until disease progression or death.
  • the chimeric poliovirus comprises lerapolturev (also known as PVSRIPO).
  • the maintenance phase is administered alone.
  • the maintenance phase is administered following the cessation of the induction phase. In some embodiments, the maintenance phase is administered 1-week, 2-weeks, 3-weeks, 4-weeks, 1 -month, 5-weeks, 6- weeks, 2-months, 3 -months, 4-months, 6-months, or greater following the cessation of the induction phase. In some embodiments, the maintenance phase comprises 2 or more treatment cycles, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 treatment cycles. In some embodiments, the maintenance phase comprises between 2 and 10 treatment cycles. In some embodiments, the maintenance phase comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, or 11 or more treatment cycles.
  • each treatment cycle of the maintenance phase is administered at least 4 weeks apart.
  • a treatment cycle of the maintenance phase is administered at the beginning of month 3, month 6, month 12, month 18, month 24, month 30, and month 36 following the start of the induction phase.
  • each treatment cycle of the maintenance phase is administered at least 4 weeks apart, at least 6 weeks apart, at least 8 weeks apart, at least 10 weeks apart, at least 12 weeks apart, or greater than 12 weeks apart.
  • each treatment cycle of the maintenance phase is administered at least 1 month apart, at least 2 months apart, at least 3 months apart, at least 4 months apart, at least 5 months apart, at least 6 months apart, or a combination thereof.
  • the subject is administered a maintenance phase alone.
  • the maintenance phase is administered following the cessation of the induction phase.
  • a method of treating a human subject having bladder cancer comprising a maintenance phase, wherein the maintenance phase comprises one or more treatment cycles, wherein each treatment cycle comprises the administration of an effective dose of a chimeric poliovirus once a week by intravesical instillation, wherein each treatment cycle lasts 1-week, 2-weeks, 3 -weeks, 4-weeks, or 6 weeks, and wherein each treatment cycle is administered 4 weeks apart, 6 weeks apart, 8 weeks apart, 10 weeks apart, 3 months apart, or 6 months apart.
  • the method is administered until disease progression or death.
  • the maintenance phase comprises 2 or more treatment cycles, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 treatment cycles.
  • the maintenance phase comprises between 2 and 10 treatment cycles. In some embodiments, the maintenance phase comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, or 11 or more treatment cycles. In some embodiments, the maintenance phase comprises 7 treatment cycles. In some embodiments, the maintenance phase is administered alone. In some embodiments, the maintenance phase is administered following the cessation of the induction phase. In some embodiments, a treatment cycle of the maintenance phase is administered at the beginning of month 3, month 6, month 12, month 18, month 24, month 30, and month 36 following the start of the induction phase.
  • the maintenance phase comprises one or more treatment cycles, wherein each treatment cycle comprises the administration of a chimeric poliovirus once a week for 3 weeks, and wherein the chimeric poliovirus is administered to the bladder via intravesical instillation.
  • the method is administered until disease progression or death.
  • the maintenance phase comprises 2 or more treatment cycles, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 treatment cycles.
  • the maintenance phase comprises between 2 and 10 treatment cycles.
  • the maintenance phase comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, or 11 or more treatment cycles.
  • each treatment cycle of the maintenance phase is administered at least 4 weeks apart.
  • a treatment cycle of the maintenance phase is administered at the beginning of month 3, month 6, month 12, month 18, month 24, month 30, and month 36 following the start of the induction phase.
  • each treatment cycle of the maintenance phase is administered at least 4 weeks apart, at least 6 weeks apart, at least 8 weeks apart, at least 10 weeks apart, at least 12 weeks apart, or greater than 12 weeks apart.
  • each treatment cycle of the maintenance phase is administered at least 1 month apart, at least 2 months apart, at least 3 months apart, at least 4 months apart, at least 5 months apart, at least 6 months apart, or a combination thereof.
  • the subject is administered a maintenance phase alone.
  • the maintenance phase is administered following the cessation of the induction phase.
  • the maintenance phase comprises one or more treatment cycles, wherein each treatment cycle comprises the administration of a chimeric poliovirus once a week for 2 weeks, and wherein the chimeric poliovirus is administered to the bladder via intravesical instillation.
  • the method is administered until disease progression or death.
  • the maintenance phase comprises 2 or more treatment cycles, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 treatment cycles.
  • the maintenance phase comprises between 2 and 10 treatment cycles.
  • the maintenance phase comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, or 11 or more treatment cycles.
  • each treatment cycle of the maintenance phase is administered at least 4 weeks apart.
  • a treatment cycle of the maintenance phase is administered at the beginning of month 3, month 6, month 12, month 18, month 24, month 30, and month 36 following the start of the induction phase.
  • each treatment cycle of the maintenance phase is administered at least 4 weeks apart, at least 6 weeks apart, at least 8 weeks apart, at least 10 weeks apart, at least 12 weeks apart, or greater than 12 weeks apart.
  • each treatment cycle of the maintenance phase is administered at least 1 month apart, at least 2 months apart, at least 3 months apart, at least 4 months apart, at least 5 months apart, at least 6 months apart, or a combination thereof.
  • the subject is administered a maintenance phase alone.
  • the maintenance phase is administered following the cessation of the induction phase.
  • the maintenance phase comprises one or more treatment cycles, wherein each treatment cycle comprises the administration of a chimeric poliovirus once a week for 1 week, and wherein the chimeric poliovirus is administered to the bladder via intravesical instillation.
  • the method is administered until disease progression or death.
  • the maintenance phase comprises 2 or more treatment cycles, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 treatment cycles.
  • the maintenance phase comprises between 2 and 10 treatment cycles.
  • the maintenance phase comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, or 11 or more treatment cycles.
  • each treatment cycle of the maintenance phase is administered at least 4 weeks apart.
  • a treatment cycle of the maintenance phase is administered at the beginning of month 3, month 6, month 12, month 18, month 24, month 30, and month 36 following the start of the induction phase.
  • the initiation of each treatment cycle of the maintenance phase is administered at least 4 weeks apart, at least 6 weeks apart, at least 8 weeks apart, at least 10 weeks apart, at least 12 weeks apart, or greater than 12 weeks apart.
  • the initiation of each treatment cycle of the maintenance phase is administered at least 1 month apart, at least 2 months apart, at least 3 months apart, at least 4 months apart, at least 5 months apart, at least 6 months apart, or a combination thereof.
  • the subject is administered a maintenance phase alone.
  • the maintenance phase is administered following the cessation of the induction phase.
  • the chimeric poliovirus is administered via intravesical instillation following a pre-wash sequence.
  • the pre-wash sequence may increase or enhance the transduction of the chimeric poliovirus.
  • the pre-wash results in the disruption of the polyanionic glycosaminoglycan (GAG) layer overlaying the epithelium.
  • the pre-wash comprises a surfactant that disrupts the GAG layer, thereby providing access to the underlying epithelium of the bladder.
  • the surfactant is a mild polar surfactant.
  • the surfactant may be, but is not limited to, Tween-80, sodium dodecyl sulfate, or cetylpyridinium chloride.
  • the pre-wash comprises a calcium ion chelator that disrupts the GAG layer, thereby providing access to the underlying epithelium of the bladder.
  • the calcium ion chelator may be, for example, polycarbophil.
  • the pre-wash sequence comprises one or more n-dodecyl-B-D- maltoside (DDM) washes and one or more saline washes.
  • DDM n-dodecyl-B-D- maltoside
  • the DDM prewash comprises between about 0.5% and about 10% DDM.
  • the pre-wash comprises between about 2% and about 6% of DDM.
  • the pre-wash comprises about 5% DDM.
  • a saline wash is administered prior to the DDM wash.
  • a saline wash is administered after the DDM wash.
  • a saline wash is administered prior to the DDM wash and then again after the saline wash.
  • the saline wash is administered and retained within the bladder for from about 2 minutes to 10 minutes. In some embodiments, the saline wash is administered and retained within the bladder for about 5 minutes. In some embodiments, the DDM wash is administered and retained within the bladder from about 2 minutes to about 25 minutes. In some embodiments, the DDM wash is administered and retained within the bladder for from about 10 minutes to about 20 minutes. In some embodiments, the DDM wash is administered and retained in the bladder for about 15 minutes +/- about 5 minutes. In some embodiments, the DDM wash is administered and retained in the bladder for about 5 minutes.
  • the patient prior to the administration of the chimeric poliovirus via intravesical instillation, is administered a pre-wash sequence in the order comprising i) a first wash comprising about 100 ml saline, ii) a second wash comprising about 75 ml 5% DDM, ii) a third wash comprising about 100 ml saline.
  • the patient prior to the administration of the chimeric poliovirus via intravesical instillation, is administered a pre-wash sequence in the order comprising i) a first wash comprising about 100 ml saline, ii) a second wash comprising about 75 ml 5% DDM, iii) a third wash comprising about 100 ml saline, wherein each saline wash is administered and retained in the bladder for about 5 minutes and the DDM wash is administered and retained in the bladder for about 15 minutes +/- about 5 minutes.
  • the chimeric poliovirus is administered in combination with one or more anti-cancer therapies.
  • the anti-cancer therapy is selected from a chemotherapeutic agent, an immunomodulatory intravesical agent, radiation therapy, surgery, a therapeutic agent, or an immune checkpoint inhibitor (ICI).
  • the anti -cancer therapy is administered by intravesical instillation.
  • the methods described herein further include the administration of an effective amount of a chemotherapeutic agent.
  • chemotherapeutic agents for use in the methods described herein include, but are not limited to, cisplatin, carboplatin, oxaliplatin, gemcitabine, mitomycin C, doxorubicin, epirubicin, docetaxel, methotrexate, vinblastine, cabazitaxel, or a combination thereof.
  • the chemotherapeutic agent is a platinum-based drug.
  • the chemotherapeutic agent is one or more platinumbased drug in combination with one or more non-platinum-based drug.
  • the platinum-based drug comprises cisplatin.
  • the platinum-based drug comprises carboplatin. In some embodiments, the platinum-based drug comprises oxaliplatin. In some embodiments, the chemotherapeutic agent is gemcitabine. In some embodiments, the chemotherapeutic agent is doxorubicin, n some embodiments, the chemotherapeutic agent is docetaxel. In some embodiments, the chemotherapeutic agent is methotrexate. In some embodiments, the chemotherapeutic agent is vinblastine. In some embodiments, the chemotherapeutic agent is cabazitaxel. In some embodiments, the chemotherapeutic agent is administered by intravesical instillation.
  • the chimeric poliovirus is administered as descried herein in combination with an intravesical agent.
  • the intravesical agent is BCG.
  • the intravesical agent comprises an oncolytic virus other than a chimeric poliovirus.
  • the chimeric poliovirus is administered as described herein in combination with radiation therapy.
  • the radiation therapy is external-beam radiation therapy.
  • the radiation therapy is intraoperative radiation therapy.
  • the radiation therapy is image guided radiation therapy.
  • the radiation therapy is intensity-modulated radiation therapy.
  • the radiation therapy is x-ray beam radiation.
  • the chimeric poliovirus is administered as described herein prior to surgery to remove or reduce the bladder cancer mass. In some embodiments, the chimeric poliovirus is administered as described herein following surgery to remove or reduce the bladder cancer mass. In some embodiments, the surgery is a transurethral resection of bladder tumors (TURBT).
  • TURBT transurethral resection of bladder tumors
  • the methods described herein further include the administration of an effective amount of a therapeutic agent.
  • Suitable therapeutic agents for use in the methods described herein include, but are not limited to, a fibroblast growth factor receptor (FGFR) inhibitor, an EZH inhibitor, an RTK inhibitor, an oncolytic virus other than a chimeric poliovirus, an IDO inhibitor, an antibody-drug conjugate, or a DNA moderator.
  • the therapeutic agent comprises an FGFR inhibitor.
  • the FGFR inhibitor is selected from rogaratinib (BAY1163877), derazantinib (ARQ 087), or a combination thereof.
  • the therapeutic agent comprises an (EZH) inhibitor.
  • the enhancer of zeste homolog 2 (EZH2) histone-lysine N-methyltransf erase enzyme inhibitor comprises tazemetostat (TAZVERIK®).
  • the therapeutic agent comprises a receptor tyrosine kinase (RTK) inhibitor.
  • RTK receptor tyrosine kinase
  • the RTK inhibitor is selected from cabozantinib (CABOMETYX®), sitravatinib (MGCD516), or a combination thereof.
  • the therapeutic agent is an oncolytic virus other than a chimeric poliovirus.
  • the oncolytic virus is selected from an adenovirus, a coxsackievirus, or a combination thereof.
  • the oncolytic virus other than a chimeric poliovirus is administered by intravesical instillation.
  • the therapeutic agent comprises an IDO inhibitor.
  • the indoleamine 2,3 dioxygenase (IDO) inhibitor is selected from entinostat (SNDX-275/MS-275), epacadostat (INCB24360), or a combination thereof.
  • the therapeutic agent is selected from CYT107, bempegaldesleukin (BEMPEG/NKTR-214), urelumab (BMS-663513), lirilumab (IPH2102), enfortumab vedotin (PADCEV®), or a combination thereof.
  • the therapeutic agent comprises a DNA moderator.
  • the DNA moderator comprises oleclumab (MEDI9447), guadecitabine (SGI-110), olaparib (LYNPARZA®), or a combination thereof.
  • the methods described herein further include the administration of an effective amount of an immune checkpoint inhibitor (ICI) to a subject with bladder cancer.
  • Suitable ICIs for use in the methods described herein include, but are not limited to, a programmed cell death -1 (PD-1) inhibitor, a programmed cell death -ligand 1 (PD-L1) inhibitor, a cytotoxic T- lymphocyte-associated protein 4 (CTLA-4) inhibitor, a lymphocyte-activation gene 3 (LAG-3) inhibitor, a T-cell immunoglobulin mucin-3 (TIM-3) inhibitor, or a T cell immunoreceptor with Ig and ITIM domains (TIGIT) program death-ligand 2 (PD-L2), a V-domain Ig suppressor of T-cell activation (VISTA), B7-H3/CD276, indoleamine 2, 3 -dioxygenase (IDO), killer immunoglobulin- like receptors (KIRs), carcinoembryonic antigen cell adhesion molecules (CEACAM
  • the administered ICI is a PD-1 inhibitor that blocks the interaction of PD-1 and PD-L1 by binding to the PD-1 receptor, and in turn inhibits immune suppression.
  • the ICI is a PD-1 ICI selected from nivolumab (Opdivo®), pembrolizumab (Keytruda®), pidilizumab (Medivation), AMP -224 (Amplimmune); sasanlimab (PF-06801591; Pfizer), spartalizumab (PDR001; Novartis), cemiplimab (Libtayo®; REGN2810; Regeneron), retifanlimab (MGA012; MacroGenics), tislelizumab (BGB-A317; BeiGene), camrelizumab (SHR-1210; Jiangsu Hengrui Medicine Company and Incyte Corporation), CS1003 (Cstone Pharmaceuticals), and dostar
  • the PD-1 inhibitor is nivolumab (Opdivo®) administered in an effective amount. In some embodiments, nivolumab is administered at 240 mg every 2 weeks or 480 mg every 4 weeks. In some embodiments, the PD-1 inhibitor is pembrolizumab (Keytruda®) administered in an effective amount. In some embodiments, pembrolizumab is administered at 200 mg every 3 weeks or 400 mg every 6 weeks. In some embodiments, the PD-1 inhibitor is cemiplimab (Libtayo®) administered in an effective amount. In some embodiments, cemiplimab is administered at 350 mg as an intravenous infusion over 30 minutes every 3 weeks.
  • the immune checkpoint inhibitor is a PD-L1 inhibitor that blocks the interaction of PD-1 and PD-L1 by binding to the PD-L1 receptor, and in turn inhibits immune suppression.
  • PD-L1 inhibitors include, atezolizumab (Tecentriq®, Genentech), durvalumab (Imfinzi®, AstraZeneca); avelumab (Bavencio®; Merck), envafolimab (KN035; Alphamab), BMS-936559 (Bristol-Myers Squibb), lodapolimab (LY3300054; Eli Lilly), cosibelimab (CK-301; Checkpoint Therapeutics), sugemalimab (CS-1001; Cstone Pharmaceuticals), adebrelimab (SHR-1316; Jiangsu HengRui Medicine), CBT-502 (CBT Pharma), and BGB-A333 (BeiGene).
  • the ICI is the PD-L1 ICI atezolizumab (Tecentriq®) administered in an effective amount. In some embodiments, atezolizumab is administered at 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks. In some embodiments, atezolizumab is administered prior to chemotherapy. In another aspect of this embodiment, the ICI is durvalumab (Imfinzi®) administered in an effective amount. In some embodiments, durvalumab is administered at 10 mg/kg every 2 weeks or 1500 mg every 4 weeks for patients that weigh more than 30 kg and 10 mg/kg every 2 weeks for patients who weigh less than 30 kg.
  • the ICI is avelumab (Bavencio®) administered in an effective amount.
  • avelumab is administered at 800 mg every 2 weeks.
  • the ICI is KN035 (Alphamab) administered in an effective amount.
  • An additional example of a PD-Ll ICI is BMS-936559 (Bristol-Myers Squibb).
  • T cell immunoreceptor with immunoglobulin and HIM domain (TIGIT) Inhibitors T cell immunoreceptor with immunoglobulin and HIM domain (TIGIT) Inhibitors
  • the immune checkpoint inhibitor is a T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT).
  • TIGIT is a promising new target for cancer immunotherapy.
  • TIGIT is upregulated by immune cells, including activated T cells, natural killer cells, and regulatory T cells.
  • TIGIT binds to two ligands, CD155 (PVR) and CD112 (PVRL2, nectin-2), that are expressed by tumor cells and antigen-presenting cells in the tumor microenvironment (Stanietsky et al., The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity. Proc Natl Acad Sci U S A 2009; 106: 17858-63).
  • TIGIT also called WUCAM, Vstm3, VSIG9
  • WUCAM WUCAM
  • Vstm3 a receptor of the Ig superfamily, which plays a critical role in limiting adaptive and innate immunity
  • TIGIT participates in a complex regulatory network involving multiple inhibitory receptors (e.g., CD96/TACTILE, CD112R/PVRIG), one competing costimulatory receptor (DNAM-1/CD226), and multiple ligands (e.g., CD155 (PVR/NECL-5), CD112 (Nectin- 2/PVRL2) (Levin et al., Vstm3 is a member of the CD28 family and an important modulator of T- cell function.
  • multiple inhibitory receptors e.g., CD96/TACTILE, CD112R/PVRIG
  • DNAM-1/CD226 competing costimulatory receptor
  • multiple ligands e.g., CD155 (PVR/NECL-5), CD112 (Nectin- 2/PVRL2) (Levin et al., Vstm3 is a member of the CD28 family and an important modulator of T- cell function.
  • the murine pan T cell marker CD96 is an adhesion receptor for CD155 and nectin-1. Biochem Biophys Res Commun 2007; 364: 959-65; Zhu et al., Identification of CD112R as a novel checkpoint for human T cells. J Exp Med 2016; 213: 167- 76).
  • TIGIT is expressed by activated CD8+ T and CD4+ T cells, natural killer (NK) cells, regulatory T cells (Tregs), and follicular T helper cells in humans (Joller et al., Cutting edge: TIGIT has T cell-intrinsic inhibitory functions. J Immunol 2011; 186: 1338-42; Wu et al., Follicular regulatory T cells repress cytokine production by follicular helper T cells and optimize IgG responses in mice. Eur J Immunol 2016; 46: 1152-61). In sharp contrast with DNAM-1/CD226, TIGIT is weakly expressed by naive T cells.
  • TIGIT is co-expressed with PD-1 on tumor antigen-specific CD8+ T cells and CD8+ tumor-infiltrating lymphocytes (TILs) in mice and humans (Chauvin et al., Tigit and PD-1 impair tumor antigen-specific CD8 + T cells in melanoma patients. J Clin Invest 2015; 125: 2046-58; Johnston et al., The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell 2014; 26 :923-37).
  • T cell immunoglobulin and mucin domaincontaining molecule-3 TIM-3
  • LAG-3 lymphocyte activation gene 3
  • TIGIT is highly expressed by Tregs in peripheral blood mononuclear cells of healthy donors and patients with cancer and further upregulated in the TME (Joller et al., Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Thl and Thl7 cell responses. Immunity 2014; 40: 569-81; Zhang et al., Genome-Wide DNA methylation analysis identifies hypomethylated genes regulated by FOXP3 in human regulatory T cells. Blood 2013; 122: 2823-36).
  • the ICI is a TIGIT inhibitor that blocks the interaction of TIGIT and CD 155 by binding to the TIGIT receptor, and in turn inhibits immune suppression.
  • TIGIT inhibitors include, but are not limited to, Etigilimab (OMP-313M32; Oncomed Pharmaceuticals); Tiragolumab (MTIG7192A; RG6058; Roche/Genentech); Vibostolimab (MK-7684; Merck); BMS-986207 (Bristol-Myers Squibb); AZD2936 (AstraZeneca); ASP8374 (Astellas/Potenza Therapeutics); Domvanalimab (AB 154; Arcus Biosciences); IBI939 (Innovent Biologies); Ociperlimab (BGB-A1217; BeiGene); EOS884448 (iTeos Therapeutics); SEA-TGT (Seattle Genetics); COM902 (Compugen); MPH-313 (OMP
  • T-cell immunoglobulin and mucin domain 3 (TIMS) inhibitors T-cell immunoglobulin and mucin domain 3 (TIMS) inhibitors
  • the immune checkpoint inhibitor is a T-cell immunoglobulin and mucin domain 3 (TIM-3) inhibitor.
  • TIM-3 is an immunoglobulin (Ig) and mucin domaincontaining cell surface molecule that was originally discovered as a cell surface marker specific to interferon (IFN-y) producing CD4 + T helper 1 (Thl) and CD8 + T cytotoxic 1 (Tel) cells (Monney et al., Thl -specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 2002; 415: 536-41).
  • Tim-3 is coregulated and co-expressed along with other immune checkpoint receptors (PD-1, Lag-3, and TIGIT) on CD4 + and CD8 + T cells (Chihara et al., Induction and transcriptional regulation of the co-inhibitory gene module in T cells. Nature 2018; 558: 454-9; DeLong et al., 11-27 and TCR stimulation promote T cell expression of multiple inhibitory receptors. ImmunoHorizons 2019; 3: 13-25).
  • Tim-3 expression specifically marks the most dysfunctional or terminally exhausted subset of CD8 + T cells (Fourcade et al., Upregulation of Tim-3 and PD-1 expression is associated with tumor antigenspecific CD8+ T cell dysfunction in melanoma patients.
  • Tim-3 Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti -tumor immunity. J Exp Med 2010; 207: 2187-94).
  • PtdSer phosphatidylserine
  • HMGB1 high-mobility group protein Bl
  • CEACAM-1 CEACAM-1
  • the ICI is a TIM-3 inhibitor that blocks the interaction of TIM-3 and galectin-9, phosphatidylserine (PtdSer), high-mobility group protein Bl (HMGB1), and/or CEACAM-1 by binding to the TIM-3 receptor, and in turn inhibits immune suppression.
  • PtdSer phosphatidylserine
  • HMGB1 high-mobility group protein Bl
  • CEACAM-1 CEACAM-1
  • TIM-3 inhibitors include, but are not limited to, Sabatolimab (MGB453; Novartis Pharmaceuticals); Cobolimab (TSR-022; Tesaro/GSK); RG7769 (Genentech); MAS-825 (Novartis); Sym023 (Symphogen A/S); BGBA425 (BeiGene); R07121661 (Hoffmann-La Roche); LY3321367 (Eli Lilly and Company); INCAGN02390 (Incyte Corporation); BMS-986258 (ONO7807, Bristol- Myers Squibb); AZD7789 (AstraZeneca); TQB2618 (Chia Tai Tianqing Pharmaceutical Group Co., Ltd.); and NB002 (Neologies Bioscience).
  • LAGS Lymphocyte activation gene- 3
  • the immune checkpoint inhibitor is a LAG-3 inhibitor.
  • LAG- 3 (CD223) is encoded by the LAG-3 gene.
  • LAG-3 is a member of the immunoglobulin superfamily (IgSF) and exerts a wide variety of biologic impacts on T cell function (Triebel et al., LAG-3, a novel lymphocyte activation gene closely related to CD4. J Exp Med 1990; 171 : 1393-405).
  • LAG- 3 is expressed on cell membranes of natural killer cells (NK), B cells, tumor-infiltrating lymphocytes (TIL), a subset of T cells, and dendritic cells (DC) (Triebel et al., LAG-3, a novel lymphocyte activation gene closely related to CD4.
  • lymphocyte activation gene 3 (LAG-3)
  • LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems.
  • LAG-3 protein binds a nonholomorphic region of major histocompatibility complex 2 (MHC class II) with greater affinity than CD 4 (Baixeras et al., Characterization of the lymphocyte activation gene 3-encoded protein. A new ligand for human leukocyte antigen class II antigens. J Exp Med 1992; 176: 327-37).
  • MHC class II major histocompatibility complex 2
  • LAG-3 is one of the various immune-checkpoint receptors that are coordinately upregulated on both regulatory T cells (Tregs) and anergic T cells, and the simultaneous blockade of these receptors can result in an enhanced reversal of this anergic state relative to the blockade of one receptor alone (Grosso et al., Functionally distinct LAG-3 and PD-1 subsets on activated and chronically stimulated CD8 T cells. J Immunol 2009; 182: 6659-69).
  • the LAG-3/MHC class II molecule interaction leads to the downregulation of CD4 + Ag-specific T cell clone proliferation and cytokine secretion (Huard et al., T cell major histocompatibility complex class II molecules down-regulate CD4 + T cell clone responses following LAG-3 binding. Eur J Immunol 1996; 26: 1180-6).
  • the checkpoint inhibitor is a LAG-3 inhibitor that blocks the interaction of LAG-3 with major histocompatibility complex 2 (MHC class II) by binding to the LAG-3 receptor, and in turn inhibits immune suppression.
  • LAG-3 inhibitors include, but are not limited to, relatlimab (BMS 986016/Ono 4482; Bristol-Myers Squibb); tebotelimab (MGD013; Macrogenics); LAG525 (Immutep, Novartis); TSR-033 (Tesaro, GlaxoSmithKline); Eftilagimod alpha (IMP321, Immutep); REGN3767 (Regeneron); INCAGN02385 (Incyte); RO7247669 (Hoffman-LaRoche); Favezelimab (Merck Sharp & Dohme); CB213 (Crescendo Biologies); FS118 (F-star Therapeutics); SYM022 (Symphogen); GSK283
  • the patient is administered a B7-H3/CD276 immune checkpoint inhibitor (ICI) such as enoblituzumab (MGA217, Macrogenics) MGD009 (Macrogenics), 1311- 8H9/omburtamab (Y-mabs), and I-8H9/omburtamab (Y-mabs), an indoleamine 2,3 -dioxygenase (IDO) ICI such as Indoximod and INCB024360, a killer immunoglobulin-like receptors (KIRs) ICI such as Lirilumab (BMS-986015), a carcinoembryonic antigen cell adhesion molecule (CEACAM) inhibitor (e.g., CEACAM-1, -3 and/or -5).
  • ICI immune checkpoint inhibitor
  • MCA217 enoblituzumab
  • MGD009 Macrogenics
  • Y-mabs 1311- 8H9/omburtamab
  • anti-CEACAM-1 antibodies are described in WO 2010/125571, WO 2013/082366 and WO 2014/022332, e.g., a monoclonal antibody 34B1, 26H7, and 5F4; or a recombinant form thereof, as described in, e.g., US 2004/0047858, U.S. Pat. No. 7,132,255 and WO 99/052552.
  • the anti- CEACAM antibody binds to CEACAM-5 as described in, e.g., Zheng et al. PLoS One. 2010 September 2; 5(9). pii: el2529 (DOI: 10: 1371/journal. pone.0021146), or cross-reacts with CEACAM-1 and CEACAM-5 as described in, e.g., WO 2013/054331 and US 2014/0271618.
  • the patient is administered an ICI directed to CD47, including, but not limited to, Hu5F9-G4 (Stanford University /Forty Seven), TI-061 (Arch Oncology), TTI-622 (Trillum Therapeutics), TTL621 (Trillum Therapeutics), SRF231 (Surface Oncology), SHR-1603 (Hengrui), OSE-172 (Boehringer Ingelheim/OSE Immunotherapeutics), NI-1701 (Novimmune TG Therapeutics), IBI188 (Innovent Biologies); CC-95251 (Celgene), CC-90002 (Celgene/Inibrx), AO-176 (Arch Oncology), ALX148 (ALX Oncology), IMM01 (ImmuneOnco Biopharma), IMM2504 (ImmuneOnco Biopharma), IMM2502 (ImmuneOnco Biopharma), IMM03 (ImmuneOnco Biopharma), IMC-002 (ImmuneOncia
  • the ICI is an inhibitor directed to CD39, including, but not limited to TTX-030 (Tizona Therapeutics), IPH5201 (Innate Pharma/AstraZeneca), SRF-617 (Surface Oncology), ES002 (Elpisciences), 9-8B (Igenica), and an antisense oligonucleotide (Secarna)
  • the ICI is an inhibitor directed to B and T lymphocyte attenuator molecule (BTLA), for example as described in Zhang et al., Monoclonal antibodies to B and T lymphocyte attenuator (BTLA) have no effect on in vitro B cell proliferation and act to inhibit in vitro T cell proliferation when presented in a cis, but not trans, format relative to the activating stimulus, Clin Exp Immunol. 2011 Jan; 163(1):77— 87, and TAB004/JS004 (Junshi Biosciences).
  • BTLA B and T lymphocyte attenuator molecule
  • the ICI is a sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) inhibitor, including, but not limited to, NC318 (an anti-Siglec-15 mAb).
  • Siglec-15 sialic acid-binding immunoglobulin-like lectin 15
  • the ICI is opdualag, a combination of the LAG-3 checkpoint inhibitor relatimab and the PD-1 inhibitor nivolumab.
  • the chimeric poliovirus for administration in the methods described herein can be administered, for example, as a pharmaceutical composition that includes an effective amount of the chimeric poliovirus for a patient, typically a human, in need of such treatment in a pharmaceutically acceptable carrier.
  • Carriers include excipients and diluents and should be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated.
  • the carrier can be inert or it can possess pharmaceutical benefits of its own.
  • the amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
  • Classes of carriers include, but are not limited to adjuvants, binders, buffering agents, coloring agents, diluents, disintegrants, excipients, emulsifiers, flavorants, gels, glidents, lubricants, preservatives, stabilizers, surfactants, solubilizer, tableting agents, wetting agents or solidifying material.
  • Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin; talc, petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers and vegetable oils.
  • Optional active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of the compound of the present invention.
  • excipients include, but are not limited, to liquids such as water, saline, glycerol, polyethylene glycol, hyaluronic acid, ethanol, and the like.
  • a biological buffer can be any solution which is pharmacologically acceptable, and which provides the formulation with the desired pH, i.e., a pH in the physiologically acceptable range.
  • buffer solutions include saline, phosphate buffered saline, Tris buffered saline, Hank’ s buffered saline, and the like.
  • permeation enhancer excipients including polymers such as: polycations (chitosan and its quaternary ammonium derivatives, poly-L- arginine, aminated gelatin); polyanions (N-carboxymethyl chitosan, poly-acrylic acid); and, thiolated polymers (carboxymethyl cellulose-cysteine, polycarbophil-cysteine, chitosanthiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione conjugates).
  • polycations chitosan and its quaternary ammonium derivatives, poly-L- arginine, aminated gelatin
  • polyanions N-carboxymethyl chitosan, poly-acrylic acid
  • thiolated polymers carboxymethyl cellulose-cysteine, polycarbophil-cysteine, chitosanthiobutylamidine, chitosan-thioglycoli
  • the excipient is selected from butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and x
  • sterile injectable suspensions are formulated according to techniques known in the art using suitable carriers, dispersing or wetting agents and suspending agents.
  • the sterile injectable formulation can also be a sterile injectable solution or a suspension in a acceptably nontoxic parenterally acceptable diluent or solvent.
  • acceptable vehicles and solvents that can be employed are water, Ringer’s solution and isotonic sodium chloride solution.
  • sterile, fixed oils, fatty esters or polyols are conventionally employed as solvents or suspending media.
  • parenteral administration can involve the use of a slow release or sustained release system such that a constant level of dosage is maintained.
  • Injectable formulations can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solubilization or suspension in liquid prior to injection, or as emulsions.
  • sterile injectable suspensions are formulated according to techniques known in the art using suitable carriers, dispersing or wetting agents and suspending agents.
  • the sterile injectable formulation can also be a sterile injectable solution or a suspension in an acceptably nontoxic parenterally acceptable diluent or solvent.
  • acceptable vehicles and solvents that can be employed are water, Ringer’s solution and isotonic sodium chloride solution.
  • sterile, fixed oils, fatty esters or polyols are conventionally employed as solvents or suspending media.
  • the pharmaceutical composition comprising the chimeric poliovirus is administered in a therapeutically effective amount by any desired mode of administration, but is typically administered as an intravesical instillation into the bladder, or alternatively, intratumor injection or infusion, or alternatively, topically applies to a tumor lesion.
  • Administration via intravesical instillation is generally known in the art.
  • Intravesical instillation is generally performed by inserting a urinary catheter to first fully drain the bladder.
  • a suspension comprising for example a chimeric poliovirus e.g. 30 mL suspension comprising lerapolturev
  • the instillation generally lasts between about 3 minutes to about 5 minutes, wherein after the instillation is finished, the catheter is removed.
  • the patient is mobilized to allow the instilled suspension comprising chimeric poliovirus to contact all inner surface area of the bladder. In some embodiments, the patient is mobilized for a period of 2 hours. In some embodiments, the patient is mobilized comprising rotating between positions selected from prone, supine, left lateral, or right lateral.
  • Administration via intratumoral injection can involve introducing the formulations of the disclosure into one or more tumor lesions of a patient through a needle or a catheter, propelled by a sterile syringe or some other mechanical device such as a continuous infusion system.
  • a formulation provided by the disclosure can be administered using a syringe, injector, pump, or any other device recognized in the art for parenteral administration.
  • lerapolturev when the chimeric poliovirus is lerapolturev, lerapolturev is formulated in 50 mM sodium phosphate in 0.9% sodium chloride, pH 7.4 with 0.2% human serum albumin (HSA) in phosphate buffered saline (PBS). Lerapolturev can be provided in sterile, single use glass vials with a flip off top containing approximately 0.5 mL of stock lerapolturev (for example, about 2.0 x 10 9 to about 1.0 x 10 10 TCID50).
  • the chimeric poliovirus may be administered in a pharmaceutical composition comprising a detergent.
  • useful detergents include, but are not limited to, n-dodecyl-B-D-maltoside (DDM), Tween-80, or SIM3.
  • DDM is a maltoside-based non-ionic detergent with a hydrophilic maltose head and a hydrophobic long chain alkyl tail. It is considered a gentle detergent that is more efficient than other detergents, such as NP-40.
  • a primary attribute of DDM is its capability to extract hydrophobic proteins while maintaining the solution-phase protein conformation. DDM also allows the protein to be reformed following denaturation.
  • Tween-80 is a nonionic surfactant and emulsifier often used in foods and cosmetics. It is derived from polyethoxylated sorbitan and oleic acid.
  • surfactants include, for example, polyoxyethylene glycol, polyoxypropylene glycol, decyl glucoside, lauryl glucoside, octyl glucoside, polyoxyethylene glycol octylphenol, Triton X-100, glycerol alkyl ester, glyceryl laurate, cocamide MEA, cocamide DEA, dodecyldimethylamine oxide, and poloxamers.
  • poloxamers examples include, poloxamers 188, 237, 338 and 407. These poloxamers are available under the trade name Pluronic® (available from BASF, Mount Olive, N.J.) and correspond to Pluronic® F-68, F-87, F-108 and F-127, respectively. Poloxamer 188 (corresponding to Pluronic® F-68) is a block copolymer with an average molecular mass of about 7,000 to about 10,000 Da, or about 8,000 to about 9,000 Da, or about 8,400 Da. Poloxamer 237 (corresponding to Pluronic® F-87) is a block copolymer with an average molecular mass of about 6,000 to about 9,000 Da, or about 6,500 to about 8,000 Da, or about 7,700 Da.
  • Pluronic® available from BASF, Mount Olive, N.J.
  • Pluronic® F-68 is a block copolymer with an average molecular mass of about 7,000 to about 10,000 Da, or about 8,000 to about 9,000 Da, or about
  • Poloxamer 338 is a block copolymer with an average molecular mass of about 12,000 to about 18,000 Da, or about 13,000 to about 15,000 Da, or about 14,600 Da.
  • Poloxamer 407 is a polyoxyethylene-polyoxypropylene triblock copolymer in a ratio of between about E101 P56 E101 to about E106 P70 E106, or about E101 P56E101, or about E106 P70 E106, with an average molecular mass of about 10,000 to about 15,000 Da, or about 12,000 to about 14,000 Da, or about 12,000 to about 13,000 Da, or about 12,600 Da.
  • surfactants that can be used in the invention include, but are not limited to, polyvinyl alcohol (which can be hydrolyzed polyvinyl acetate), polyvinyl acetate, Vitamin E-TPGS, poloxamers, cholic acid sodium salt, dioctyl sulfosuccinate sodium, hexadecyltrimethyl ammonium bromide, saponin, TWEEN® 20, TWEEN® 80, sugar esters, Triton X series, L-a-phosphatidylcholine (PC), 1 ,2-dipalmitoylphosphatidycholine (DPPC), oleic acid, sorbitan trioleate, sorbitan mono-oleate, sorbitan monolaurate, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monooleate, natural lecithin, oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, lauryl polyoxy
  • the detergent is administered by intravesical instillation. In some embodiments, the administration of detergent increases cellular viral intake. In some embodiments, the detergent is administered one or more times as a pre-wash. In some embodiments, the detergent is administered with a chimeric poliovirus by intravesical instillation. In some embodiments, the pharmaceutical composition described herein further comprises detergent. In some embodiments, the detergent comprises Tween-80. In some embodiments, the detergent comprises DDM. In some embodiments, the detergent comprises SIM-3. In some embodiments, the detergent is administered by intravesical instillation in a solution at a concentration between at about 0.1% and at about 1.0%.
  • the detergent is administered by intravesical instillation in a solution at a concentration of at about 0.1%. In some embodiments, the detergent is administered by intravesical instillation in a solution at a concentration of at about 0.5%. In some embodiments, the detergent is administered by intravesical instillation in a solution at a concentration of at about 1.0%.
  • the chimeric poliovirus may be administered in a pharmaceutical composition comprising a hydrogel.
  • the hydrogel is a thermal hydrogel.
  • the hydrogel is a reverse-thermal hydrogel, wherein the hydrogel is a liquid when cold and converts to a gel form at body temperature.
  • Reverse-thermal hydrogels are known in the art and include, for example, RTGelTM manufactured by Urogen Pharma.
  • a treatment regimen comprising intravesical instillation administration of a chimeric poliovirus described herein provides enhanced objective response rate (ORR) in the patients receiving the treatment.
  • ORR is generally defined as the proportion of patients achieving a complete response (CR) or partial response (PR) per RECIST 1.1.
  • Examples of an objective response (OR) includes a complete response (CR), which is the disappearance of all signs of the tumor in response to treatment and a partial response (PR), which is a decrease in the size of a tumor in response to treatment.
  • the OR is a CR.
  • the OR is a PR.
  • the ORR is an important parameter to demonstrate the efficacy of a treatment and it serves as a primary or secondary endpoint in clinical trials.
  • the induction cycle is repeated if no objective response rate (ORR) is exhibited by the patient.
  • ORR objective response rate
  • the induction cycle is repeated if no complete response (CR) is exhibited by the patient.
  • the induction cycle is repeated if no partial response (PR) is exhibited by the patient.
  • the maintenance phase is administered following an objective response rate (ORR) exhibited by the patient following the cessation of the induction phase. In some embodiments, the maintenance phase is administered following a complete response (CR) exhibited by the patient following the cessation of the induction phase.
  • ORR objective response rate
  • CR complete response
  • a treatment regimen comprising intravesical instillation administration of a chimeric poliovirus described herein provides enhanced clinical benefit rate (CBR) in the patients receiving the treatment.
  • CBR is generally defined as the proportion of patients with CR (for any duration), PR (for any duration) or SD (> 6 months) per RECIST 1.1.
  • a treatment regimen comprising intravesical instillation administration of a chimeric poliovirus described herein provides lengthened duration of response (DOR) in the patients receiving the treatment.
  • DOR is generally defined as the time from OR (per RECIST 1.1) until unequivocal disease progression or death, whichever occurs first.
  • a treatment regimen comprising intravesical instillation administration of a chimeric poliovirus described herein provides lengthened progression-free survival (PFS) in the patients receiving the treatment.
  • PFS is generally defined as the time (measured in number of months) from the date of assigning patient ID number until date of documented radiologic disease progression per RECIST 1.1 or death due to any cause, whichever come first.
  • a treatment regimen comprising intravesical instillation administration of a chimeric poliovirus described herein provides enhanced overall survival (OS) in the patients receiving the treatment.
  • OS is generally defined as the time (measured in number of months) from the date of assigning patient ID number until death due to any cause.
  • a treatment regimen comprising intravesical instillation administration of a chimeric poliovirus described herein provides alterations from baseline in immune function markers in blood samples and/or tissue, as data permits, in the patients receiving the treatment.
  • a treatment regimen comprising intravesical instillation administration of a chimeric poliovirus described herein provides alterations from baseline in tumor biomarkers in tumor samples, as data permits, in the patients receiving the treatment.
  • a treatment regimen comprising intravesical instillation administration of a chimeric poliovirus provides alterations in genetic markers in tumor biopsies and/or blood samples that correlate with response in the patients receiving the treatment.
  • a treatment regimen comprising intravesical instillation administration of a chimeric poliovirus provides alterations in cytologic markers in tumor biopsies and/or blood samples that correlate with response in the patients receiving the treatment.
  • a treatment regimen comprising intravesical instillation administration of a chimeric poliovirus provides alterations in histologic markers in tumor biopsies and/or blood samples that correlate with response in the patients receiving the treatment.
  • a treatment regimen comprising intravesical instillation administration of a chimeric poliovirus provides alterations in molecular markers in tumor biopsies and/or blood samples that correlate with response in the patients receiving the treatment.
  • a treatment regimen comprising intravesical instillation administration of a chimeric poliovirus described herein provides reduced recurrence rate of bladder tumor formation.
  • a treatment regimen comprising intravesical instillation administration of a chimeric poliovirus described herein provides decreased need for bladder tumor resection surgeries including but not limited to transurethral resection of bladder tumor (TURBT) or cystectomy.
  • a treatment regimen comprising intravesical instillation administration of a chimeric poliovirus described herein provides decreased frequency of bladder tumor resection surgeries including but not limited to TURBT or cystectomy.
  • a treatment regimen comprising intravesical instillation administration of a chimeric poliovirus described herein provides lengthened relapse-free survival (RFS).
  • the purpose of this study was to characterize the potency of lerapolturev after exposure to various insults including urine, saliva, detergent, and various pH levels.
  • the positive control sample for each condition was lerapolturev with regular growth media for the entire length of the experiment.
  • the negative control sample for each condition was formulation buffer with regular growth media.
  • the mock sample for each condition was formulation buffer with adjusted growth media (e.g., Tween-80, DDM, pH, Urine, Saliva) while the experimental sample(s) were lerapolturev with adjusted growth media (Table 3). Total incubation time lasted 2 hours.
  • lerapolturev was diluted to multiplicities of infectivity (MOI) of 20, 6.6, or 2.0 using regular growth media. Dilutions were then added to U-87 MG (U87) human primary glioblastoma cell seeded plates in triplicate and incubated for 42 ⁇ 4 hours.
  • MOI multiplicities of infectivity
  • MTS assay cytotoxicity assay was conducted wherein MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3- carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium)/ phenazine methosulfate (PMS) reagent was added to samples which is reduced by NAD(P)H-dependent cellular oxidoreductase enzymes to produce formazan, a compound with a max absorbance value of 490 nm in PBS.
  • MTS 3-(4,5-dimethylthiazol-2-yl)-5-(3- carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium
  • PMS phenazine methosulfate
  • the amount of formazan product released is proportional to the number of viable cells present in each sample and inversely related to the degree of lerapolturev infectivity (i.e., low absorbance ⁇ low cell viability/greater lerapolturev infectivity; high absorbance ⁇ high cell viability/lower lerapolturev infectivity).
  • the sample absorbance values at 490 nM were analyzed on a Spectramax ID5 multi-mode microplate reader.
  • IFN-beta (IFN-P) enzyme-linked-immunosorbent assay (ELISA) immodulation assay was developed to examine the effect of various chemical insults including detergent, pH, urine, and saliva on the potency of lerapolturev infection and cellular response.
  • Assay variability was evaluated using three different lerapolturev lots with multiple MOI (2, 6.6, 20). Coefficient of variation (CV%) ranged from 28% to 111% from plate to plate. Intraplate variability was significantly lower for MOI 6.6 and MOI 20. This suitability and assay variability assay demonstrated that MOI 6.6 or 20 had consistently high IFN-P response and were the optimal concentrations for immunomodulation testing (Table 5). Table 5. Assay variability values
  • growth media was added to the plate for up to 44 hours (including the various incubation times with lerapolturev).
  • MTS reagent was incubated with cells for 4 hours then SDS was added and absorbance measurements at 490 nm were collected using a Spectramax ID5 multi-mode microplate reader.
  • A375 melanoma cells (ATCC, CR-1619) were treated with lerapolturev at different MOI (2, 6.6, 20) for 5 min, 15 min, 30 min, 60 min, 2 hr, or 24 hr. After reaching the specific incubation time, growth media containing virus were removed, cells were washed and incubated with virus free growth media for 48 hr total (including the various incubation times with lerapolturev). At 48 hours, supernatant samples were collected, and IFN-P secretion was analyzed using the human IFN-P Quantikine ELISA Kit (R&D Systems, DIFNB0).
  • This substudy is to evaluate different methods of administration of PVSRIPO into tumors located within the bladder mucosa.
  • Two cohorts of patients will be enrolled in this portion of the study, including Cohort E and F. Both Cohort E and F will evaluate the administration of PVSRIPO monotherapy in patients with recurrent NMIBC intended for TURBT or cystectomy; patients enrolled in Cohort E will receive PVSRIPO via intravesical instillation while patients enrolled in Cohort F will receive PVSRIPO via intratumoral injection via cystoscopy.
  • Cohort E has been designed to evaluate 2 different dose levels of PVSRIPO using a 3+3 dose escalation approach ( Figure 4).
  • Three patients will initially be treated with a total dose of 2 xlO 9 TCID50 (Low Dose Cohort E) administered by intravesical instillation and the frequency of DLTs assessed.
  • Each dose of PVSRIPO will be administered in a final volume of 30 ml by intravesical instillation.
  • a urinary catheter will be inserted into the urethra under aseptic conditions according to local hospital protocol and the bladder drained completely. Using a catheter adapter with the syringe, the PVSRIPO suspension will then be instilled into the bladder via the catheter over a period of 3 to 5 minutes.
  • the catheter After instillation the catheter will be removed and the patient instructed to retain the instilled suspension in the bladder for a period of 2 hours. During this period, care should be taken to ensure that the instilled suspension has sufficient contact with the whole mucosal surface of the bladder. The patient should be encouraged to mobilize or, if lying down, to rotate between prone, supine, left lateral, and right lateral positions every 15 minutes.
  • the patient After 2 hours the patient should void the instilled suspension directly into a toilet. After bladder evacuation, the next first voided urine sample should be collected for PVSRIPO Shedding. The patient should be advised to limit their fluid intake for 4 hours prior to instillation and until bladder evacuation is permitted (i.e. 2 hours after instillation).
  • the decision to escalate/de-escalate the PVSRIPO dose will be based on the presence of DLTs observed during the 14 days following administration of PVSRIPO in consultation with the independent Data Safety Monitoring Committee (DSMC).
  • DSMC Data Safety Monitoring Committee
  • MTD maximally tolerated dose
  • the purpose of Cohort F is to assess if PVSRIPO infection of cells within the bladder mucosa is facilitated by pretreatment with a detergent able to disrupt the GAG layer of the epithelium.
  • a chimeric poliovirus is to be administered by intravesical instillation in several different potential administration schedules.
  • exemplary administration schedules of a chimeric poliovirus are illustrated in FIG. 5A - D.
  • a chimeric poliovirus e.g., lerapolturev
  • FIG. 5A exemplary administration schedules of a chimeric poliovirus
  • a chimeric poliovirus e.g., lerapolturev
  • a chimeric poliovirus is administered by intravesical instillation on the first day of each week of two consecutive 6-week induction cycles (FIG. 5B).
  • a chimeric poliovirus (e.g., lerapolturev) is administered by intravesical instillation on the first day of each week of a 6-week induction cycle which comprises an induction phase followed by intravesical instillation administration of a chimeric poliovirus (e.g., lerapolturev) on the first day of the first three weeks of months 3, 6, 12, 18, 24, 30, and 36 months following the beginning of the induction cycle, which comprises a maintenance phase (FIG. 5C).
  • the one or more maintenance phases comprise three weekly intravesical instillation administrations of a chimeric poliovirus in maintenance cycles occurring at months 1, 3, 9, 15, 21, 27, and 33 of the maintenance phase.
  • a chimeric poliovirus (e.g., lerapolturev) is administered by intravesical instillation on the first day of each week of a 6-week induction cycle which comprises an induction phase followed by intravesical instillation administration of a chimeric poliovirus (e.g., lerapolturev) on the first day of the first week of months 3, 6, 12, 18, 24, 30, and 36 months following the beginning of the induction cycle, which comprises a maintenance phase (FIG. 5C).
  • the one or more maintenance phases comprise one intravesical instillation administration of a chimeric poliovirus in maintenance cycles occurring at months 1, 3, 9, 15, 21, 27, and 33 of the maintenance phase.
  • the patient prior to each lerapolturev administration, is administered a series of pre-washes comprising saline and 5% DDM.
  • the intravesical instillation of PVSRIPO occurs after a sequence of a 100 ml saline wash, a 75 ml 5% DDM wash, and a 100 ml saline wash.

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Abstract

La présente invention concerne des méthodes améliorées destinées à traiter le cancer de la vessie, notamment le cancer de la vessie non invasif sur le plan musculaire (NMIBC), chez un sujet humain, consistant à administrer par instillation intravésicale, au patient, une dose élevée d'une construction de poliovirus chimérique comprenant une souche de poliovirus Sabin de type I avec un site d'entrée ribosomique interne (IRES) de rhinovirus 2 humain (HRV2) dans la région non traduite 5' de poliovirus entre la structure en feuille de trèfle d'un poliovirus et le cadre ouvert de lecture d'un poliovirus (un "poliovirus chimérique"). Selon l'invention, le poliovirus chimérique est administré par instillation intravésicale dans un régime de traitement particulier comprenant une phase d'induction et une phase de maintenance.
PCT/US2023/011184 2022-01-19 2023-01-19 Méthodes de traitement de cancers de la vessie par instillation intravésicale d'un poliovirus chimérique WO2023141236A2 (fr)

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